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Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice
Abstract
Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo.
... Many models overexpress human mutant APP in the form of single transgenic mice (such as PDAPP [68], APP/Ld [69], Tg2576 [38], TgCRND8 [39], APP23 [40], tgAPP ArcSwe [70], APP-Au [71], or APP E693∆ [42]). In addition, several bigenic lines expressing combinations of APP and PS1/PS2 (e.g., 5XFAD [46], APPswe/PS1dE9 [72], APP/PS1 [49], PS2APP [73], APP/PS1KI [52]), APP and Tau (such as APP/Tau [55]), or triple transgenic mice expressing APP, PS1/2, and Tau (e.g., 3xTg [74], 5XFAD/PS19 [56], or TauPS2APP [75]) have been generated. While most of these models present abundant extracellular amyloid plaque pathology and associated inflammatory changes, modelling significant neuron loss remained often less or only partially successful. ...
... Accelerated plaque formation together with neurofibrillary degeneration and neuronal loss has been described in Tg2576 mice crossed to the VLW lines expressing human 4-repeat Tau containing a triple mutation [55]. While neither neurofibrillary tangle formation nor significant neuron loss in CA1 has been reported in the single-transgenic Tg2576 model [66], stereology-based neuron counts revealed significantly reduced neuron numbers in the CA1 and entorhinal cortex in APP/Tau mice [55]. ...
... Accelerated plaque formation together with neurofibrillary degeneration and neuronal loss has been described in Tg2576 mice crossed to the VLW lines expressing human 4-repeat Tau containing a triple mutation [55]. While neither neurofibrillary tangle formation nor significant neuron loss in CA1 has been reported in the single-transgenic Tg2576 model [66], stereology-based neuron counts revealed significantly reduced neuron numbers in the CA1 and entorhinal cortex in APP/Tau mice [55]. ...
Transgenic mouse models represent an essential tool for the exploration of Alzheimer’s disease (AD) pathological mechanisms and the development of novel treatments, which at present provide only symptomatic and transient effects. While a variety of mouse models successfully reflects the main neuropathological hallmarks of AD, such as extracellular amyloid-β (Aβ) deposits, intracellular accumulation of Tau protein, the development of micro- and astrogliosis, as well as behavioral deficits, substantial neuron loss, as a key feature of the disease, seems to be more difficult to achieve. In this review, we summarize information on classic and more recent transgenic mouse models for AD, focusing in particular on loss of pyramidal, inter-, and cholinergic neurons. Although the cause of neuron loss in AD is still a matter of scientific debate, it seems to be linked to intraneuronal Aβ accumulation in several transgenic mouse models, especially in pyramidal neurons.
... The arrow in the left panel indicates a neuron. Reproduced from Ribé et al. (2005) with permission from Elsevier. ...
... Although most studies using double-and triple-transgenic mice have shown a unidirectional relationship between APP/Aβ expression and increased tau pathology, there is an example in which amyloid deposition is increased by mutant tau expression. In that work, Tg2576 expressing APP with the K670N/M671L Swedish mutation was crossed with a mutant tau line, tau VLW , containing G272V, P301L and R406W mutations (Fig. 3h) Ribé et al., 2005). Not only does the expression of APP Swe lead to increased tau phosphorylation and accumulation in the sarkosyl-insoluble fraction , but expression of the tau mutant also increases the numbers of amyloid plaques by up to 5-fold at 16 months of age (Ribé et al., 2005). ...
... In that work, Tg2576 expressing APP with the K670N/M671L Swedish mutation was crossed with a mutant tau line, tau VLW , containing G272V, P301L and R406W mutations (Fig. 3h) Ribé et al., 2005). Not only does the expression of APP Swe lead to increased tau phosphorylation and accumulation in the sarkosyl-insoluble fraction , but expression of the tau mutant also increases the numbers of amyloid plaques by up to 5-fold at 16 months of age (Ribé et al., 2005). The double-transgenic animals also suffer from more pronounced neuronal loss than either APP Swe or tau VLW littermates (Ribé et al., 2005). ...
Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro , we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.
... Human MAPT knock-in models have also been developed, and these models produce tau pathology, but only very late in the murine life span (~15 months) [2][3][4]. Jiang,Page 5 Multiple groups have explored crossing transgenic APP mouse over-expression models with tau mouse models [12][13][14][15][16][17][18][19]. The results generally show that A accelerates tau pathology [12][13][14]16]. ...
... These over-expression models consistently observe that the presence of A pathology enhances the accumulation of MAPT pathology, neurodegeneration and cognitive loss [12][13][14][15][16][17]. These same studies indicate that the presence of MAPT pathology either doesn't change the accumulation of A pathology or decreases it [12][13][14][15][16][17], with only one initial study suggesting that MAPT pathology increases A pathology [18]. A closer look at the MAPT and A pathologies suggest further parallels between the APP NL-G-F /MAPT P301S cross and AD in humans. ...
The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APP NL−G−F MAPT P301S mouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APP NL−G−F /MAPT P301S mouse model also showed strong accumulation of N ⁶ -methyladenosine (m ⁶ A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m ⁶ A from mRNA, respectively. Thus, the APP NL−G−F /MAPT P301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.
... ; https://doi.org/10.1101/2023.03. 28.534515 doi: bioRxiv preprint Multiple groups have explored crossing transgenic APP mouse over-expression models with tau mouse models [12][13][14][15][16][17][18][19]. The results generally show that A accelerates tau pathology [12][13][14]16]. ...
... These over-expression models consistently observe that the presence of A pathology enhances the accumulation of MAPT pathology, neurodegeneration and cognitive loss [12][13][14][15][16][17]. These same studies indicate that the presence of MAPT pathology either doesn't change the accumulation of A pathology or decreases it [12][13][14][15][16][17], with only one initial study suggesting that MAPT pathology increases A pathology [18]. A closer look at the MAPT and A pathologies suggest further parallels between the APP NL-G-F /MAPT P301S cross and AD in humans. ...
The study for the pathophysiology study of Alzheimer's disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular beta-amyloid (A-beta) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APPNL-G-F MAPTP301S mouse that at 6 months of age exhibits robust A-beta plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A-beta pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A-beta accumulation. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Thus, the APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging.
... However, these mice, when used in conjunction with APP mutations, help to provide a better model for the human AD condition. Examples of mouse models modeling both amyloid and tau pathology include the Tg2576/JNPL3 cross ( Lewis et al., 2001), crosses of the Tg2576 and VLW(tau) mice ( Pérez et al., 2005;Ribé et al., 2005), hAPP (Swe)/wildtype human Tau ( Chabrier et al., 2014), hAPP NLI /Tau(P301L) ( Paulson et al., 2008), APP23/B6P301L ( Bolmont et al., 2007), APP-V717I/TauP301L ( Terwel et al., 2008), and the 3xTg-AD mouse ( Oddo et al., 2003). These models display both amyloid and tau pathology, with the 3xTg-AD mouse including mutations in PS1. ...
... Evidence is conflicting as to whether this also leads to an increase in amyloid. Certain hAPP/tau mice such as the JNPL3 × Tg2576 cross ( Lewis et al., 2001) and the APP23/B6P301L ( Bolmont et al., 2007) showed no difference in plaque load compared to the sole hAPP mice while other models showed an increase in amyloid pathology ( Ribé et al., 2005). Although both Aβ and tau pathology are noted in the AD brain, the progression of tau pathology specifically has been shown to better correlate with dementia than Aβ ( Braak and Braak, 1991;Ingelsson et al., 2004;Morris et al., 2014). ...
The brains of those with Alzheimer's disease have amyloid and tau pathology; thus, mice modeling AD should have both markers. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (htau) strains (referred to as dual Tg). Behavior was assessed at both 3.5 and 7 months, and biochemical differences were assessed at 8 months. Additionally, mice were placed on zinc (Zn) water or standard lab water in order to determine the role of this essential biometal. Behavioral measures examined cognition, emotion, and aspects of daily living. Transgenic mice (dual Tg and htau) showed significant deficits in spatial memory in the Barnes Maze at both 3.5 and 7 months compared to controls. At 7 months, dual Tg mice performed significantly worse than htau mice (p < 0.01). Open field and elevated zero maze (EZM) data indicated that dual Tg and htau mice displayed behavioral disinhibition compared to control mice at both 3.5 and 7 months (p < 0.001). Transgenic mice showed significant deficits in activities of daily living, including burrowing and nesting, at both 3.5 and 7 months compared to control mice (p < 0.01). Dual Tg mice built very poor nests, indicating that non-cognitive tasks are also impacted by AD. Overall, dual Tg mice demonstrated behavioral deficits earlier than those shown by the htau mice. In the brain, dual Tg mice had significantly less free Zn compared to control mice in both the dentate gyrus and the CA3 of the hippocampus (p < 0.01). Dual Tg mice had increased tangles and plaques in the hippocampus compared to htau mice and the dual Tg mice given Zn water displayed increased tangle pathology in the hippocampus compared to htau mice on Zn water (p < 0.05). The dual Tg mouse described here displays pathology reminiscent of the human AD condition and is impaired early on in both cognitive and non-cognitive behaviors. This new mouse model allows researchers to assess how both amyloid and tau in combination impact behavior and brain pathology.
... Previous reports have suggested that amyloid-b is capable of altering tau biology in mice, rats, non-human primates and humans (Sigurdsson et al., 1997;Price and Morris, 1999;Gotz et al., 2001;Lewis et al., 2001;Delacourte et al., 2002;Ribé et al., 2005;Bolmont et al., 2007;Hurtado et al., 2010;Seino et al., 2010;Mairet-Coello et al., 2013;Forny-Germano et al., 2014;Héraud et al., 2014;Barthélemy et al., 2016;Manassero et al., 2016;Bennett et al., 2017;He et al., 2018). To analyse tau aggregates biochemically, brain lysate was first run on an SDD-AGE gel to assess the level of high and low molecular weight tau protein (Fig. 2D). ...
... All previous studies that have analysed a human tau lowering therapy have been done so solely in the presence of tau pathology. However, given the observation of synergy between tau and amyloid-b across multiple systems (Ribé et al., 2005;Bolmont et al., 2007;Hurtado et al., 2010;Seino et al., 2010;Forny-Germano et al., 2014;Héraud et al., 2014;Bennett et al., 2017), we asked whether a human tau reduction approach, which has been shown to be highly effective in human tau transgenic mice (Santacruz et To test this idea, we genetically lowered the human tau transgene in APP Â rTg4510 mice that develop both amyloid-b plaques and neurofibrillary tangles in an age-dependent manner (Bennett et al., 2017). DOX treatment was equally effective at lowering human MAPT/tau mRNA and protein in both the rTg4510 and APP Â rTg4510 lines (Figs 1 and 2). ...
Several studies have now supported the use of a tau lowering agent as a possible therapy in the treatment of tauopathy disorders, including Alzheimer's disease. In human Alzheimer's disease, however, concurrent amyloid-β deposition appears to synergize and accelerate tau pathological changes. Thus far, tau reduction strategies that have been tested in vivo have been examined in the setting of tau pathology without confounding amyloid-β deposition. To determine whether reducing total human tau expression in a transgenic model where there is concurrent amyloid-β plaque formation can still reduce tau pathology and protect against neuronal loss, we have taken advantage of the regulatable tau transgene in APP/PS1 × rTg4510 mice. These mice develop both neurofibrillary tangles as well as amyloid-β plaques throughout the cortex and hippocampus. By suppressing human tau expression for 6 months in the APP/PS1 × rTg4510 mice using doxycycline, AT8 tau pathology, bioactivity, and astrogliosis were reduced, though importantly to a lesser extent than lowering tau in the rTg4510 alone mice. Based on non-denaturing gels and proteinase K digestions, the remaining tau aggregates in the presence of amyloid-β exhibit a longer-lived aggregate conformation. Nonetheless, lowering the expression of the human tau transgene was sufficient to equally ameliorate thioflavin-S positive tangles and prevent neuronal loss equally well in both the APP/PS1 × rTg4510 mice and the rTg4510 cohort. Together, these results suggest that, although amyloid-β stabilizes tau aggregates, lowering total tau levels is still an effective strategy for the treatment of tau pathology and neuronal loss even in the presence of amyloid-β deposition.
... When transgenic mice that develop amyloid or tau pathology are cross bred, they typically demonstrate that amyloid can enhance tauopathy compared to mice transgenic only for human tau. [4][5][6][7][8][9][10][11][12] In most of these models, there is a clear temporal pattern of amyloid plaques emerging before tauopathy. In 3xTg mice, in which amyloid pathology precedes tauopathy, treatment with anti-Aβ immunotherapy not only depletes amyloid deposits but also reduces tauopathy. ...
INTRODUCTION
Alzheimer's disease (AD) is a progressive neurodegenerative disease in which extracellular aggregates of the amyloid beta (Aβ) peptide precede widespread intracellular inclusions of the microtubule‐associated protein tau. The autosomal dominant form of AD requires mutations that increase production or aggregation of the Aβ peptide. This has led to the hypothesis that amyloid deposition initiates downstream responses that lead to the hyperphosphorylation and aggregation of tau.
METHODS
Here we use a novel approach, somatic gene transfer via intravenous adeno‐associated virus (AAV), to further explore the effects of pre‐existing amyloid deposits on tauopathy. APP+PS1 mice, which develop amyloid deposits at 3 to 6 months of age, and non‐transgenic littermates were injected at 8 months of age intravenously with AAV‐PHP.eB encoding P301L human tau. Tissue was collected at 13 months and tauopathy was assessed.
RESULTS
Total human tau expression was observed to be relatively uniform throughout the brain, reflecting the vascular route of AAV administration. Phospho‐tau deposition was not equal across brain regions and significantly increased in APP+PS1 mice compared to non‐transgenic controls. Interestingly, the rank order of phospho‐tau deposition of affected brain regions in both genotypes paralleled the rank order of amyloid plaque deposits in APP+PS1 mice. We also observed significantly increased MAPT RNA expression in APP+PS1 mice compared to non‐transgenic despite equal AAV transduction efficiency between groups.
DISCUSSION
This model has advantages over prior approaches with widespread uniform human tau expression throughout the brain and the ability to specify the stage of amyloidosis when the tau pathology is initiated. These data add further support to the amyloid cascade hypothesis and suggest RNA metabolism as a potential mechanism for amyloid‐induced tauopathy.
... The study used double transgenic female APP SWE -Tau P301L mice (Taconic, Rensselaer, NY). These mice were reported to develop brain lesions typical of AD, specifically amyloid plaques and NFTs [51]. The animals were used in accordance with animal use protocol HC-AD-029 and were overseen by the Histo-Chem's Institutional Animal Care and Use Committee. ...
Background: Alzheimer’s disease (AD) is the most prevalent age-related dementia, and, despite numerous attempts to halt or reverse its devastating progression, no effective therapeutics have yet been confirmed clinically. However, one class of agents that has shown promise is certain metal chelators. Objective: For the novel assessment of the effect of oral administration of 1,10-phenanthroline-5-amine (PAA) on the severity of amyloid plaque load, we used a transgenic (Tg) mouse model with inserted human autosomally dominant (familial) AD genes: amyloid-β protein precursor (AβPP) and tau. Methods: AβPP/Tau transgenic mice that model AD were allotted into one of two groups. The control group received no treatment while the experimental group received PAA in their drinking water starting at 4 months of age. All animals were sacrificed at 1 year of age and their brains were stained with two different markers of amyloid plaques, Amylo-Glo+ and HQ-O. Results: The control animals exhibited numerous dense core plaques throughout the neo- and allo- cortical brain regions. The experimental group treated with PAA, however, showed 62% of the amyloid plaque burden seen in the control group. Conclusions: Oral daily dosing with PAA will significantly reduce the amyloid plaque burden in transgenic mice that model AD. The underlying mechanism for this protection is not fully known; however, one proposed mechanism involves inhibiting the “metal-seeding” of Aβ.
... In this context, LiCl [180], MW181 and SB239063 [137], SM07883 [139], and Fasudil [143] demonstrate significant reduction in levels of sarcosylinsoluble tau. Meanwhile, with Tideglusib [130], the levels in the selected age groups were pointed out to be too low to be reliably quantified [192,193]. BAY-61 [140,142] and AZD0530 [181] were also demonstrated to reduce detergent and trisbuffered saline (TBS) insoluble fractions. In the remaining studies, although the data from immunoblots was consistent with immunohistochemical staining, demonstrating efficient reduction in tau hyperphosphorylation [137,180], yet the quantification of insoluble fractions was not performed. ...
Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein described in Alzheimer's disease (AD), highlighting the role of PKs in neurodegeneration. The therapeutic potential of protein kinase inhibitors (PKIs)) and protein phosphatase 2 A (PP2A) activators in AD has recently been explored in several preclinical and clinical studies with variable outcomes. Where a number of preclinical studies demonstrate a visible reduction in the levels of phospho-tau in transgenic tauopathy models, no reduction in neurofibrillary lesions is observed. Amongst the few PKIs and PP2A activators that progressed to clinical trials, most failed on the efficacy front, with only a few still unconfirmed and potential positive trends. This suggests that robust preclinical and clinical data is needed to unequivocally evaluate their efficacy. To this end, we take a systematic look at the results of preclinical and clinical studies of PKIs and PP2A activators, and the evidence they provide regarding the utility of this approach to evaluate the potential of targeting tau hyperphosphorylation as a disease modifying therapy.
... Neuronal loss in these regions closely correlates with cognitive impairments [306,307]. Various AD transgenic mouse models replicate the neuronal loss seen in AD [308][309][310][311][312]. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood–brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.
... This result is relevant considering that amyloid pathology is critical for tau-mediated hippocampal and amygdala dysfunction and memory deficits in non-demented subjects [23]. It is plausible, however, that tau affects amyloid pathology-associated dystrophic neurites or neurodegeneration [62,63], and could antagonize the effects of Aβ on hyperexcitation causing aberrant neuronal activity [46,64]. The underlying mechanisms by which Aβ affects tau pathology are still unclear, but neuronal activity, microglia, and genetic variants could be critical players [65][66][67]. ...
Alzheimer’s disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory- and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-β (Aβ) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein ( APP Sw,Ind ) and/or microtubule-associated protein tau ( MAPT ) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to Aβ pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to Aβ/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (e.g., APOE , BIN1 , CD33 , CLU , PICALM , PLCG 2, PTK2B , TREM2 , SORL1 , USP6NL ) differentially expressed in the hippocampus and/or BLA of APP/Tau mice, indicating that this APP/Tau model exhibits transcriptional alterations linked to known molecular determinants of AD development. In conclusion, simultaneous development of Aβ and tau neuropathologies in this double APP/Tau transgenic mouse model reproduces synaptic, behavioral, and molecular alterations associated with AD pathophysiology in a region-specific manner. Our findings highlight region-specific pathological effects of Aβ and tau in excitatory neuronal circuits mediating emotional and memory processing, providing evidence that both factors and their molecular cascades should be considered in future AD preventive and therapeutic strategies.
Graphical abstract
Age-dependent vulnerability of memory and emotional neural circuits in response to tau and Aβ pathologies.
... We should, however, also acknowledge that some studies have disputed the idea of a linear model in which tau pathology is purely a downstream effect of Aβ, and instead propose that there may be a reciprocal interaction between Aβ and tau (130,131). Overexpressing human tau in an AD mouse model with APP/PS1 mutations led to an increase in plaque size but no Downloaded from http://portlandpress.com/neuronalsignal/article-pdf/doi/10.1042/NS20220086/940533/ns-2022-0086.pdf by UK user on 10 December 2022 change in synapse loss when compared to APP/PS1 mice lacking the tau transgene (131). In another study, the deletion of tau significantly decreased levels of soluble and insoluble Aβ in APP/PS1 mutant mice, likely via an impairment of β-secretase cleavage of APP due to a disruption in BACE1 trafficking (132). ...
The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-β at synapses is the key driver of Alzheimer’s disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer’s research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-β levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-β at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-β levels may lend further support.
... By nine to twelve months, marked neuronal loss occurs along with atrophy of the hippocampus and entorhinal cortex [43]. Furthermore, APP/Tau double transgenic mice expressing human mutant APP and human mutant tau show neuronal loss in the entorhinal cortex after nine months of age compared with APP alone transgenic mice, tau alone transgenic mice, and wild-type mice [44]. These reports suggest that the progression of tau pathology is essential for neuronal loss that closely reproduces clinical AD pathology. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that requires further pathological elucidation to establish effective treatment strategies. We previously showed that amyloid β (Aβ) toxic conformer with a turn at positions 22–23 is essential for forming highly toxic oligomers. In the present study, we evaluated phenotypic changes with aging in AD model AppNL-P-F/NL-P-F (NL-P-F) mice with Swedish mutation (NL), Iberian mutation (F), and mutation (P) overproducing E22P-Aβ, a mimic of toxic conformer utilizing the knock-in technique. Furthermore, the role of the toxic conformer in AD pathology was investigated. NL-P-F mice produced soluble toxic conformers from an early age. They showed impaired synaptic plasticity, glial cell activation, and cognitive decline, followed by the accumulation of Aβ plaques and tau hyperphosphorylation. In addition, the protein expression of hypoxia-inducible factor (HIF)-1α was increased, and gene expression of HIF-3α was decreased in NL-P-F mice. HIF dysregulation due to the production of soluble toxic conformers may be involved in AD pathology in NL-P-F mice. This study could reveal the role of a highly toxic Aβ on AD pathogenesis, thereby contributing to the development of a novel therapeutic strategy targeting the toxic conformer.
... The two peptides, Aβ 1-42 and NH 2 -26-44, the smaller and more toxic one, inhibit ANT-1-dependent ADP/ATP exchange and together further aggravate mitochondrial dysfunction by exacerbating ANT-1 impairment. Certainly, these data are in line with results obtained from histological analyses conducted in the AD brain and in mouse models, which point out the synergy between plaques and tangles [91][92][93][94]. In order to identify the plausible mechanistic interaction of truncated Aβ and NH 2-tau peptides in impaired neuronal mitochondria, data on reciprocal coimmunoprecipitations on synapticenriched mitochondrial fractions suggest that an NH 2-tau/ANT-1/Aβ/CypD complex exists within an authentic cellular context in AD but not in age-matched nondemented controls. ...
Alzheimer's disease (AD), certainly the most widespread proteinopathy, has as classical neuropathological hallmarks, two groups of protein aggregates: senile plaques and neurofibrillary tangles. However, the research interest is rapidly gaining ground in a better understanding of other pathological features, first, of all the mitochondrial dysfunctions. Several pieces of evidence support the hypothesis that abnormal mitochondrial function may trigger aberrant processing of amyloid progenitor protein or tau and thus neurodegeneration. Here, our aim is to emphasize the role played by two 'bioenergetic' proteins inserted in the mitochondrial membranes, inner and outer, respectively, that is, the adenine nucleotide translocator (ANT) and the voltage-dependent anion channel (VDAC), in the progression of AD. To perform this, we will magnify the ANT and VDAC defects, which are measurable hallmarks of mitochondrial dysfunction, and collect all the existing information on their interaction with toxic Alzheimer's proteins. The pathological convergence of tau and amyloid β-peptide (Aβ) on mitochondria may finally explain why the therapeutic strategies used against the toxic forms of Aβ or tau have not given promising results separately. Furthermore, the crucial role of ANT-1 and VDAC impairment in the onset/progression of AD opens a window for new therapeutic strategies aimed at preserving/improving mitochondrial function, which is suspected to be the driving force leading to plaque and tangle deposition in AD.
... Interestingly, behavioral phenotypes occur earlier and more severe in several APP x tau crosses than in their single-Tg siblings [194,195]. APP/tau mice showed a significant reduction in the number of neurons within CA1 and the entorhinal cortex [196]. Crossing the 5xFAD model with PS19 tau mice [62] resulted in a clear aggravation of the tau pathology with a robust hippocampal atrophy and severe loss of neurons in the CA1 layer [197]. ...
Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery.
... For instance, Ribe et al. (2005) generated a double transgenic mouse (APP sw -tau vlw ) obtained by crossing Tg2576 (expressing human APP with the double Swedish mutation) and VLW (expressing human 4-repeat tau containing a triple mutation, G272V, P301L and R406W) lines. They showed that, with age, the coexpression of human APP and Tau triggers neurofibrillary degeneration and neuronal loss in selective brain limbic areas [12]. Likewise, Oddo et al. (2003) generated the 3xTg-AD model with mutations in APP, PS1 and MAPT [13]. ...
Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.
... Aβ plaques and NFTs relate to neurodegeneration, supported by increased expression of these pathological hallmarks in the neuronal cell body and in abnormal neuronal processes adjoining hippocampal and cortical Aβ deposits (Duyckaerts et al., 1998;Lewis et al., 2001;Ribe et al., 2005;Cohen et al., 2013;Koss et al., 2016;Park et al., 2019). Alternatively, the vascular hypothesis claims that cerebrovascular diseases are prevalent comorbidities in AD, which induce cognitive impairment and dementia (Humpel and Marksteiner, 2005). ...
Amyloidogenicity and vascular dysfunction are the key players in the pathogenesis of Alzheimer’s disease (AD), involving dysregulated cellular interactions. An intricate balance between neurons, astrocytes, microglia, oligodendrocytes and vascular cells sustains the normal neuronal circuits. Conversely, cerebrovascular diseases overlap neuropathologically with AD, and glial dyshomeostasis promotes AD-associated neurodegenerative cascade. While pathological hallmarks of AD primarily include amyloid-β (Aβ) plaques and neurofibrillary tangles, microvascular disorders, altered cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability induce neuronal loss and synaptic atrophy. Accordingly, microglia-mediated inflammation and astrogliosis disrupt the homeostasis of the neuro-vascular unit and stimulate infiltration of circulating leukocytes into the brain. Large-scale genetic and epidemiological studies demonstrate a critical role of cellular crosstalk for altered immune response, metabolism, and vasculature in AD. The glia associated genetic risk factors include APOE, TREM2, CD33, PGRN, CR1, and NLRP3, which correlate with the deposition and altered phagocytosis of Aβ. Moreover, aging-dependent downregulation of astrocyte and microglial Aβ-degrading enzymes limits the neurotrophic and neurogenic role of glial cells and inhibits lysosomal degradation and clearance of Aβ. Microglial cells secrete IGF-1, and neurons show a reduced responsiveness to the neurotrophic IGF-1R/IRS-2/PI3K signaling pathway, generating amyloidogenic and vascular dyshomeostasis in AD. Glial signals connect to neural stem cells, and a shift in glial phenotype over the AD trajectory even affects adult neurogenesis and the neurovascular niche. Overall, the current review informs about the interaction of neuronal and glial cell types in AD pathogenesis and its critical association with cerebrovascular dysfunction.
... Using the same line of P301S tau transgenic mice, a trend towards a higher extracellular amyloid plaque load was detected in PDAPP/Tau bigenic mice [8], while no evidence for increased Aβ pathology was evident in 5XFAD/PS19 mice at either 3 or 9 months of age [9]. However, it has to be noted that an up to 5-fold increased amyloid load was observed in 16-month-old Tg2576 mice that have been crossed with a tau transgenic line harboring a triple-mutant tau (G272V, P310L, R406W) [34]. ...
The relationship between the two most prominent neuropathological hallmarks of Alzheimer’s Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ4–42 is among the most abundant. To understand whether soluble Aβ4–42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4–42 mouse model of AD, exclusively expressing Aβ4–42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.
... Only a few studies have focused on the effects of tau pathology on Aβ accumulation. A previous study showed a fivefold increase of Aβ plaque burden in the brains of double transgenic mice expressing mutated APP and tau in comparison with the mice expressing mutated APP only [44]. Another study demonstrated that tau deletion led to a reduction of Aβ plaque by 50% in mice expressing mutated APP and PS1 [45]. ...
Background
The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive.
Methods
Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored.
Results
We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice.
Conclusion
These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.
... A few studies have reported the development of animal models that show both plaques and tangles [8][9][10][11][12] . These models showing coexisting expression of mutated forms of APP, tau gene (MAPT), and occasionally also PSEN1 or PSEN2, display plaques and tangles in the same model. ...
Alzheimer’s disease (AD) is mainly characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFTs). While the recent 5xFAD AD mouse model exhibits many AD-related phenotypes and a relatively early and aggressive amyloid β production, it does not show NFTs. Here, we developed and evaluated a novel AD mouse model (6xTg-AD, 6xTg) by crossbreeding 5xFAD mice with mice expressing mutant (P301L) tau protein (MAPT). Through behavioral and histopathological tests, we analyzed cognitive changes and neuropathology in 6xTg mice compared to their respective parental strains according to age. Spatial memory deficits occurred in 6xTg mice at 2 months of age, earlier than they occurred in 5xFAD mice. Histopathological data revealed aggressive Aβ42 and p-tau accumulation in 6xTg mice. Microglial activation occurred in the cortex and hippocampus of 6xTg mice beginning at 2 months. In 6xTg model mice, the synaptic loss was observed in the cortex from 4 months of age and in the hippocampus from 6 months of age, and neuronal loss appeared in the cortex from 4 months of age and in the hippocampus 6 months of age, earlier than it is observed in the 5xFAD and JNPL3 models. These results showed that each pathological symptom appeared much faster than in their parental animal models. In conclusion, these novel 6xTg-AD mice might be an advanced animal model for studying AD, representing a promising approach to developing effective therapy.
... Certain APP/Tau mice overexpressing hAPP sw together with hTau P301L (JNPL3/Tg2576 and APP23/B6P301L) show no differences in Aβ plaque load compared with single hAPP sw transgenic mice (Bolmont et al., 2007;Lewis et al., 2001). However, 16 mo Tg2576/VLW mice displayed enhanced amyloid deposition (Ribé et al., 2005). Our data demonstrate that no changes in Aβ deposition are present in J20/VLW mice compared with J20 animals at either 8 mo or 12 mo, although an increase in Aβ deposition at later stages in double transgenic mice cannot be discarded. ...
Alzheimer’s disease comprises amyloid-β (Aβ) and hyperphosphorylated Tau (P-Tau) accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimer’s disease Neuropathology (NDAN) defines a novel clinical entity with Aβ and Tau pathologies, but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models are currently unavailable for NDAN. We show that J20/VLW mice, accumulating Aβ and P-Tau, exhibit preserved hippocampal rhythmic activity and cognition, altered in J20 and VLW animals. Furthermore, we show that coexistence with Aβ renders a particular P-Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model to understand the mechanisms driving cognitive preservation in NDAN and suggest that a differential P-Tau pattern in hippocampal interneurons prevents GABAergic septohippocampal innervation loss and alterations in local field potentials, avoiding cognitive deficits.
... Until recently, Nrgn KO mice have been sugimpaired working/reference memory,31,35,38,39,[42][43][44][45] and abnormal sensorimotor gating 46,47 overlap with those of Nrgn KO mice, which suggests the potential of Nrgn KO as a model of AD. Considering this, a decrease in NRGN in the brains of AD model mice 48 and AD patients 6,7 may potentially explain some of the phenotypes or symptoms, respectively. ...
Aims
Neurogranin (NRGN) is a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. Recent studies suggest that NRGN is involved in neuropsychiatric disorders, including schizophrenia, ADHD, and Alzheimer's disease. Previous behavioral studies of Nrgn knockout (Nrgn KO) mice identified hyperactivity, deficits in spatial learning, impaired sociability, and decreased prepulse inhibition, which suggest that these mice recapitulate some symptoms of neuropsychiatric disorders. To further validate Nrgn KO mice as a model of neuropsychiatric disorders, we assessed multiple domains of behavioral phenotypes in Nrgn KO mice using a comprehensive behavioral test battery including tests of homecage locomotor activity and nesting behavior.
Methods
Adult Nrgn KO mice (28‐54 weeks old) were subjected to a battery of comprehensive behavioral tests, which examined general health, nesting behavior, neurological characteristics, motor function, pain sensitivity, locomotor activity, anxiety‐like behavior, social behavior, sensorimotor gating, depression‐like behavior, and working memory.
Results
The Nrgn KO mice displayed a pronounced decrease in nesting behavior, impaired motor function, and elevated pain sensitivity. While the Nrgn KO mice showed increased locomotor activity in the open field test, these mice did not show hyperactivity in a familiar environment as measured in the homecage locomotor activity test. The Nrgn KO mice exhibited a decreased number of transitions in the light‐dark transition test and decreased stay time in the center of the open field test, which is consistent with previous reports of increased anxiety‐like behavior. Interestingly, however, these mice stayed on open arms significantly longer than wild‐type mice in the elevated plus maze. Consistent with previous studies, the mutant mice exhibited decreased prepulse inhibition, impaired working memory, and decreased sociability.
Conclusions
In the current study, we identified behavioral phenotypes of Nrgn KO mice that mimic some of the typical symptoms of neuropsychiatric diseases, including impaired executive function, motor dysfunction, and altered anxiety. Most behavioral phenotypes that had been previously identified, such as hyperlocomotor activity, impaired sociability, tendency for working memory deficiency, and altered sensorimotor gating, were reproduced in the present study. Collectively, the behavioral phenotypes of Nrgn KO mice detected in the present study indicate that Nrgn KO mice are a valuable animal model that recapitulates a variety of symptoms of neuropsychiatric disorders, such as schizophrenia, ADHD, and Alzheimer's disease.
... Most importantly, clinical trials with therapeutics that aim to reduce the levels of amyloid-β in the brain have failed 93 , which leads to questions of the role of Aβ in AD. In addition, in double transgenic mice expressing both human mutant Tau and APP, greater Aβ deposition and NFT-like formation with increased neuronal loss are found when compared with APP or Tau single transgenic mice, indicating that Tau may accelerate amyloid deposition 94 . Interestingly, human secreted Tau increases Aβ production in human neurons 95 . ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.
... It is well known that different neuropathological lesions such as Aβ, NFTs, or Lewy bodies can co-exist in the brains of AD patients (Braak and Braak, 1997;Hamilton, 2000), predicting cross protein interactions. Indeed, several studies have shown that the interaction between Aβ and tau can exaggerate AD pathology (Ribé et al., 2005;Bennett et al., 2017;He et al., 2018;Vergara et al., 2019) and that amyloid deposition, preceding the NFT formation, can actively influence tau spreading to neocortical regions (Braak and Braak, 1997;Hardy and Selkoe, 2002;Jacobs et al., 2018;Vogel et al., 2020). Furthermore, oligomeric forms of Aβ were found to be abundant in synapses of AD patients early in the disease before the appearance of phospo-tau at later stages, suggesting that soluble Aβ oligomers in synaptic terminals are associated with dementia onset and may initiate a cascade that drives phosphorylated tau accumulation and its synaptic spread (Bilousova et al., 2016). ...
Alzheimer’s disease (AD) is pathologically defined by extracellular accumulation of amyloid-β (Aβ) peptides generated by the cleavage of amyloid precursor protein (APP), strings of hyperphosphorylated Tau proteins accumulating inside neurons known as neurofibrillary tangles (NFTs) and neuronal loss. The association between the two hallmarks and cognitive decline has been known since the beginning of the 20th century when the first description of the disease was carried out by Alois Alzheimer. Today, more than 40 million people worldwide are affected by AD that represents the most common cause of dementia and there is still no effective treatment available to cure the disease. In general, the aggregation of Aβ is considered an essential trigger in AD pathogenesis that gives rise to NFTs, neuronal dysfunction and dementia. During the process leading to AD, tau and Aβ first misfold and form aggregates in one brain region, from where they spread to interconnected areas of the brain thereby inducing its gradual morphological and functional deterioration. In this mini-review article, we present an overview of the current literature on the spreading mechanisms of Aβ and tau pathology in AD since a more profound understanding is necessary to design therapeutic approaches aimed at preventing or halting disease progression.
... For example, crossing APP (Tg2576 model) with tau producing P301L mice (JNPL3 model) led to dramatic acceleration of tangle formation in EC, olfactory cortex and amygdala but, remarkably, also in regions that rarely exhibit tangles in JNPL3 controls 42 Larger plaque areas and enhanced neuritic dystrophy were also described upon crossing APP/PS1 mice with the wild-type tau expressing rTg21221 line 45 . Furthermore, enhanced plaque burden was reported in a cross between Tg2576 mice and the VLW-tau model 46 . In contrast, cross-breeding of 5xFAD with Thy-Tau22 mice resulted in dramatic reductions in plaque burden, probably due to activation of phagocytic microglia 47 . ...
Patients with Alzheimer’s disease (AD) present with both extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. For many years, the prevailing view of AD pathogenesis has been that changes in Aβ precipitate the disease process and initiate a deleterious cascade involving tau pathology and neurodegeneration. Beyond this ‘triggering’ function, it has been typically presumed that Aβ and tau act independently and in the absence of specific interaction. However, accumulating evidence now suggests otherwise and contends that both pathologies have synergistic effects. This could not only help explain negative results from anti-Aβ clinical trials but also suggest that trials directed solely at tau may need to be reconsidered. Here, drawing from extensive human and disease model data, we highlight the latest evidence base pertaining to the complex Aβ–tau interaction and underscore its crucial importance to elucidating disease pathogenesis and the design of next-generation AD therapeutic trials.
... To date, most research has focused on a reduction in Aβ, and relatively few reports have targeted Tau conformers. Importantly, histological analyses in AD brains demonstrate synergism between these pathologies [181][182][183][184]. One issue that needs to be addressed in this field is the potential toxicity associated with Aβ and Tau immunotherapy following the binding of Aβ and Tau owing to the cellular uptake of antibodies, which destabilizes the microtubules, resulting in cytoskeletal integrity and high intervention with axonal transport [184]. ...
Central nervous system (CNS) disorders represent a broad spectrum of brain ailments with short- and long-term disabilities, and nanomedicine-based approaches provide a new therapeutic approach to treating CNS disorders. A variety of potential drugs have been discovered to treat several neuronal disorders; however, their therapeutic success can be limited by the presence of the blood-brain barrier (BBB). Furthermore, unique immune functions within the CNS provide novel target mechanisms for the amelioration of CNS diseases. Recently, various therapeutic approaches have been applied to fight brain-related disorders, with moderate outcomes. Among the various therapeutic strategies, nanomedicine-based immunotherapeutic systems represent a new era that can deliver useful cargo with promising pharmacokinetics. These approaches exploit the molecular and cellular targeting of CNS disorders for enhanced safety, efficacy, and specificity. In this review, we focus on the efficacy of nanomedicines that utilize immunotherapy to combat CNS disorders. Furthermore, we detailed summarize nanomedicine-based pathways for CNS ailments that aim to deliver drugs across the BBB by mimicking innate immune actions.
Overview of how nanomedicines can utilize multiple immunotherapy pathways to combat CNS disorders.
... Nevertheless, in human brains, it has been found that the deposition of Aβ occurs approximately ten years before the formation of NFTs [42]. Interestingly, it has been observed that the deposition of phosphorylated tau was accelerated following Aβ injection into the brain of APP transgenic (Tg) mice [13] and APP Tg × tau Tg mice [43]. In addition to this, mutations of familial AD (FAD) genes including PSEN and APP have been found to increase the formation of Aβ by increasing the generation of total Aβ or Aβ42. ...
Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the characteristics of this devastating disorder include the progressive and disabling deficits in the cognitive functions including reasoning, attention, judgment, comprehension, memory, and language.
Objective: In this article, we have focused on the recent progress that has been achieved in the development of an effective AD vaccine.
Summary: Currently, available treatment options of AD are limited to deliver short-term symptomatic relief only. A number of strategies targeting amyloid-beta (Aβ) have been developed in order to treat or prevent AD. In order to exert an effective immune response, an AD vaccine should contain adjuvants that can induce an effective anti-inflammatory T helper 2 (Th2) immune response. AD vaccines should also possess the immunogens which have the capacity to stimulate a protective immune response against various cytotoxic Aβ conformers. The induction of an effective vaccine’s immune response would necessitate the parallel delivery of immunogen to dendritic cells (DCs) and their priming to stimulate a Th2-polarized response. The aforesaid immune response is likely to mediate the generation of neutralizing antibodies against the neurotoxic Aβ oligomers (AβOs), and also anti-inflammatory cytokines which is like to prevent the AD-related inflammation.
Conclusion: Since there is an age-related decline in the immune functions, therefore vaccines are more likely to prevent AD instead of providing treatment. AD vaccines might be an effective approach due to the convenience and in order to avoid the treatment-related huge expense.
... The presence of Aβ pathology in the human brain also appears to enhance the seeding potential of tau; when tested in an in vitro seeding assay, tissue homogenate from human brains with tauopathy but no plaques was less efficacious at seeding tau aggregation than was homogenate from brains with both tauopathy and plaques (Bennett et al., 2017). It should be noted, though, that there is also evidence that the presence of tau pathology can exacerbate Aβ deposition in transgenic mice (Ribé et al., 2005;Leroy et al., 2012); in this way, Aβ and tau may form a positive feedback loop, versus Aβ acting exclusively upstream of tau. ...
Alzheimer's disease (AD) is characterized neuropathologically by progressive neurodegeneration and by the presence of amyloid plaques and neurofibrillary tangles. These plaques and tangles are composed, respectively, of amyloid-beta (Aβ) and tau proteins. While long recognized as hallmarks of AD, it remains unclear what causes the formation of these insoluble deposits. One theory holds that prion-like templated misfolding of Aβ and tau induces these proteins to form pathological aggregates, and propagation of this misfolding causes the stereotyped progression of pathology commonly seen in AD. Supporting this theory, numerous studies have been conducted in which aggregated Aβ, tau, or α-synuclein is injected intracerebrally into pathology-free host animals, resulting in robust formation of pathology. Here, we review this literature, focusing on in vivo intracerebral seeding of Aβ and tau in mice. We compare the results of these experiments to what is known about the seeding and spread of α-synuclein pathology, and we discuss how this research informs our understanding of the factors underlying the onset, progression, and outcomes of proteinaceous pathologies.
... Reproduced with permission from [236] Verkhratsky et al. P301L TET-off Tangles [224] 7TauTg Tangles [113] Tg2576 × JNPL3 (APP SWE ) Plaques and Tangles [158] Tg2576 and VLW Plaques and Tangles [228] 3xTg-AD Plaques and Tangles [202] Tg478 K670M/N671L Plaques [132] ...
Alzheimer’s disease is the most common cause of dementia. Cellular changes in the brains of the patients suffering from Alzheimer’s disease occur well in advance of the clinical symptoms. At the cellular level, the most dramatic is a demise of neurones. As astroglial cells carry out homeostatic functions of the brain, it is certain that these cells are at least in part a cause of Alzheimer’s disease. Historically, Alois Alzheimer himself has recognised this at the dawn of the disease description. However, the role of astroglia in this disease has been understudied. In this chapter, we summarise the various aspects of glial contribution to this disease and outline the potential of using these cells in prevention (exercise and environmental enrichment) and intervention of this devastating disease.
... Tau pathology is implicated in non-Alzheimer disease pathophysiology (suspected non-Alzheimer disease pathophysiology -SNAP). In AD many studies demonstrated a synergism between tangles and plaques, with abnormal tau that enhances Ab toxicity and vice-versa (57,58). ...
The nerve growth factor (NGF) belongs to a family of proteins termed neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. Today, NGF is well recognized to mediate a large number of trophobiological actions resulting in neu-rotrophic, immunotrophic and/or metabotrophic effects. The pathobiology of neurodegenerative diseases , including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of altering the brain levels of neurotrophins and in particular NGF. The involvement of NGF and its TrkA receptor in these pathologies and the recent promising results of NGF therapies are presented and discussed. Biomed Rev 2018; 29:xx-xx. ________________________________________________________________________
... Furthermore, intraneuronal Tau alterations precede aggregated Aβ deposition in the presymptomatic stages (Braak stage 1-3) of AD (36), and Tau tangles develop temporally either before or independently of Aβ plaques (37)(38)(39). Moreover, greater Aβ deposition and NFT-like formation with increased neuronal loss was found in double-transgenic mice expressing both human mutant Tau and APP than in single-transgenic mice expressing APP or Tau, suggesting that Tau might accelerate amyloid deposition (40). Recently, it has been reported that human secreted Tau increases Aβ production in human neurons (41). ...
Significance
Our most recent reports demonstrate that δ-secretase (AEP) cleaves both APP and Tau, promoting Ab and neurofibrillary tangle formation. Depletion of δ-secretase diminishes Alzheimer’s disease (AD) pathologies and restores cognitive functions in AD mouse models. Moreover, we found that C/EBPβ, an inflammatory cytokine or Ab-activated transcription factor, dictates δ-secretase expression during aging. Overexpression of C/EBPβ facilitates AD pathologies via upregulating δ-secretase, whereas depletion of C/EBPβ reduces AD pathologies. In the current study, we examined the pathological roles of the C/EBPβ/δ-secretase axis in different AD mouse models, at different time points, and in different brain regions and found that this pathway plays a critical role in mediating AD pathologies and cognitive function. Hence, C/EBPβ/δ-secretase spatiotemporally mediates AD pathogenesis.
... Tau pathology is implicated in non-Alzheimer disease pathophysiology (suspected non-Alzheimer disease pathophysiology -SNAP). In AD many studies demonstrated a synergism between tangles and plaques, with abnormal tau that enhances Ab toxicity and vice-versa (57,58). ...
Abstract
This work highlights recent studies in epigenetic mechanisms that play a role in alcoholism, a complex multifactorial disorder. A large body of evidence has shown that alcohol can modify gene expression through epigenetic processes, namely DNA methylation and nucleosomal remodeling via histone modifications. In that vein, chronic ethanol exposure modifies DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol-mediated chromatin remodeling in the brain promotes the transition from use to abuse and addiction. Unravelling the multiplex pattern of molecular modifications induced by ethanol involves the ability to develop new, epigenetic processes-targeting therapies for alcoholism and drug addiction.
... Furthermore, intraneuronal Tau alterations precede aggregated Aβ deposition in Braak-stage 1-3 in the pre-symptomatic stages of AD [25], and Tau tangles develop temporally either before or independent of Aβ plaques [26][27][28]. Moreover, in double transgenic mice expressing both human mutant Tau and APP, greater Aβ deposition and NFT-like formation with increased neuronal loss is found when compared with APP or Tau single transgenic mice, indicating that Tau may accelerate amyloid deposition [29]. Most recently, it has been reported that human secreted Tau increases Aβ production in human neurons [30]. ...
δ-Secretase, an age-dependent asparagine protease, cleaves both amyloid precursor protein (APP) and Tau and is required for amyloid plaque and neurofibrillary tangle pathologies in Alzheimer’s disease (AD). However, whether δ-secretase activation is sufficient to trigger AD pathogenesis remains unknown. Here we show that the fragments of δ-secretase-cleavage, APP (586–695) and Tau(1–368), additively drive AD pathogenesis and cognitive dysfunctions. Tau(1–368) strongly augments BACE1 expression and Aβ generation in the presence of APP. The Tau(1–368) fragment is more robust than full-length Tau in binding active STAT1, a BACE1 transcription factor, and promotes its nuclear translocation, upregulating BACE1 and Aβ production. Notably, Aβ-activated SGK1 or JAK2 kinase phosphorylates STAT1 and induces its association with Tau(1–368). Inhibition of these kinases diminishes stimulatory effect of Tau(1–368). Knockout of STAT1 abolishes AD pathologies induced by δ-secretase-generated APP and Tau fragments. Thus, we show that Tau may not only be a downstream effector of Aβ in the amyloid hypothesis, but also act as a driving force for Aβ, when cleaved by δ-secretase.
... Whilst these have their advantages, they also have a number of limitations. These types of models do not accurately recapitulate human pathology as they do not develop the robust tauopathy or neuronal cell death that is seen in human disease without the addition of extra transgenes such as tau ( Ribé et al., 2005). ...
Alzheimer's disease is the most common form of dementia, it is estimated to affect over 40 million people worldwide. Classically, the disease has been characterized by the neuropathological hallmarks of aggregated extracellular amyloid-β and intracellular paired helical filaments of hyperphosphorylated tau. A wealth of evidence indicates a pivotal role for the innate immune system, such as microglia, and inflammation in the pathology of Alzheimer's disease. The over production and aggregation of Alzheimer's associated proteins results in chronic inflammation and disrupts microglial clearance of these depositions. Despite being non-excitable, microglia express a diverse array of ion channels which shape their physiological functions. In support of this, there is a growing body of evidence pointing to the involvement of microglial ion channels contributing to neurodegenerative diseases such as Alzheimer's disease. In this review, we discuss the evidence for an array of microglia ion channels and their importance in modulating microglial homeostasis and how this process could be disrupted in Alzheimer's disease. One promising avenue for assessing the role that microglia play in the initiation and progression of Alzheimer's disease is through using induced pluripotent stem cell derived microglia. Here, we examine what is already understood in terms of the molecular underpinnings of inflammation in Alzheimer's disease, and the utility that inducible pluripotent stem cell derived microglia may have to advance this knowledge. We outline the variability that occurs between the use of animal and human models with regards to the importance of microglial ion channels in generating a relevant functional model of brain inflammation. Overcoming these hurdles will be pivotal in order to develop new drug targets and progress our understanding of the pathological mechanisms involved in Alzheimer's disease.
Introduction
The study of the pathophysiology study of Alzheimer’s disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration.
Methods
The humanized APPNL-G-F knock-in mouse line was crossed to the PS19 MAPTP301S, over-expression mouse line to create the dual APPNL-G-F/PS19 MAPTP301S line. The resulting pathologies were characterized by immunochemical methods and PCR.
Results
We now report on a double transgenic APPNL-G-F/PS19 MAPTP301S mouse that at 6 months of age exhibits robust A plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of A pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. MAPT pathology neither changed levels of amyloid precursor protein nor potentiated A accumulation. Interestingly, study of immunofluorescence in cleared brains indicates that microglial inflammation was generally stronger in the hippocampus, dentate gyrus and entorhinal cortex, which are regions with predominant MAPT pathology. The APPNL-G-F/MAPTP301S mouse model also showed strong accumulation of N⁶-methyladenosine (m⁶A), which was recently shown to be elevated in the AD brain. m⁶A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m⁶A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively.
Discussion
Our understanding of the pathophysiology of Alzheimer’s disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular -amyloid (A) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. The APPNL-G-F/MAPTP301S mouse recapitulates many features of AD pathology beginning at 6 months of aging, and thus represents a useful new mouse model for the field.
Alzheimer disease is one of the most challenging demons in our society due to its very high prevalence and its clinical manifestations which cause deterioration of cognition, intelligence, and emotions - the very capacities that distinguish Homo sapiens from other animal species. Besides the personal, social, and economical costs, late stages of AD are vivid experiences for the family, relatives, friends, and general observers of the progressive ruin of an individual who turns into a being with lower mental and physical capacities than less evolved species. A human brain with healthy cognition, conscience, and emotions can succeed in dealing with most difficulties that life may pose. Without these capacities, the same person probably cannot. Due, in part, to this emotional impact, the absorbing study of AD has generated, over the years, a fascinating and complex story of theories, hypotheses, controversies, fashion swings, and passionate clashes, together with tremendous efforts and achievements geared to improve understanding of the pathogenesis and treatment of the disorder. Familal AD is rare and linked to altered genetic information associated with three genes. Sporadic AD (sAD) is much more common and multifactorial. A major point of clinical discussion has been, and still is, establishing the differences between brain aging and sAD. This is not a trivial question, as the neuropathological and molecular characteristics of normal brain aging and the first appearance of early stages of sAD-related pathology are not easily distinguishable in most individuals. Another important point is confidence in assigning responsibility for the beginning of sAD to a few triggering molecules, without considering the wide number of alterations that converge in the pathogenesis of aging and sAD. Genetic risk factors covering multiple molecular signals are increasing in number. In the same line, molecular pathways are altered at early stages of sAD pathology, currently grouped under the aegis of normal brain aging, only to increase massively at advanced stages of the process. Sporadic AD is here considered an inherent, natural part of human brain aging, which is prevalent in all humans, and variably present or not in a few individuals in other species. The progression of the process has devastating effects in a relatively low percentage of human beings eventually evolving to dementia. The continuum of brain aging and sAD implies the search for a different approach in the study of human brain aging at the first stages of the biological process, and advances in the use of new technologies aimed at slowing down the molecular defects underlying human brain aging and sAD at the outset, and transfering information and tasks to AI and coordinated devices.
This chapter gives a simple overview of the chemicals known to create some of the symptoms of Alzheimer’s disease. Some of the commonly used transgenic models available for research are also mentioned. In some cases a chemical otherwise known to induce Alzheimer’s disease like system can exacerbate disease pathology in a transgenic model system. Each model has its own benefits and limitations. The chapter also describes some of the theories that describe the induction and development of Alzheimer's disease. New models to develop traits of Alzheimer disease pathology may be derived from these hypotheses in order to understand the Alzheimer disease progression and enable identification of lead compounds for clinical trials.
Alzheimer's disease (AD) is characterized by the extracellular aggregation of the Amyloid-ß peptide (Aß) in amyloid plaques and by the intraneuronal accumulation of aggregated hyperphosphorylated tau (pTau) in neurofibrillary tangles (NFTs). To date, our understanding of the molecular pathways and cellular circuits involved in the toxic effects of Aß and pTau is still incomplete. To better understand how pTau exerts its toxicity in AD, we used two complementary localized proteomics approaches: (i) a quantitative proteomics method performed on microdissected NFTs from AD patients, and (ii) an Affinity-Purification Mass Spectrometry method to identify NFT-associated proteins that specifically bind to pTau. In this study, we identified 542 proteins in NFTs, and confirmed that 75 proteins present in NFTs interacted with pTau. In addition, we also identified 13 novel interactors. Among these, SCRN1 was selected for further characterization. Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons, at both early and late stages of AD. Furthermore, this association between SCRN1 and pTau was unique to AD, and was not observed in other tauopathies. Thus, SCRN1 may be a novel therapeutic target and serve as a useful biomarker to distinguish AD from other tauopathies. In conclusion, we hope that proteomic studies such as ours will lead to a better understanding of the disease mechanisms occurring in AD and other tauopathies.
Alzheimer’s disease (AD) accounts for 60–80 % of dementia cases worldwide and has no effective treatment currently, presenting a pressing need to search for new anti-AD agents. One of the AD therapeutic options is to improve the cognitive impairment by restoring the characteristic cholinergic deficiency with acetylcholinesterase (AChE) inhibitors. It has been previously shown that the natural Amaryllidaceae alkaloids galanthamine and haemanthidine from Lycoris radiata inhibit the ace-2 gene expression in transgenic CL4176 C. elegans. The aim of this project was to screen and characterize the Amaryllidaceae alkaloids extracted from twelve Lycoris species. Different type of alkaloids were tentatively identified by UPLC-QTOF-MS method. Three alkaloids lycorine, lycoramine and galanthamine were quantified in these species. These Lycoris alkaloids were shown to reduce the toxicity and the neurodegeneration induced by the neuronal expression of amyloid β in transgenic CL2355 C. elegans by a serotonin assay and to collectively inhibit the ace-2 gene expression by both qRT-PCR and BLItz™ analyses. The active species includes L. chinensis, L. caldwellii, L. squamigera and L. incarnate. The alkaloid metabolite profiling results indicate that these active species are rich in different alkaloids, which are potential markers for anti-Alzheimer disease.
Alzheimer’s disease (AD) is an emerging major health and socioeconomic burden worldwide. It is characterized by neuronal loss, memory loss and cognitive impairment in the aging population. Despite several scientific advancements over the past five decades, the underlying molecular mechanism of the disease progression is yet unknown. Glycogen synthase kinase-3β (GSK-3β) has huge implications on brain function causing molecular pathologies, neuronal damage and impairment of brain performance in AD. It is one of the key players in signaling pathways for normal brain functioning and a critical molecular link between amyloid beta (Aβ) and tau neurofibrillary tangles (NFTs). GSK-3β activation is driven by phosphorylation of tau(τ) protein which results in disruption of neuronal synaptic activities and formation of neuronal plaques. Although, the accumulation of Aβ plaques and intracellular tangles of hyperphosphorylated tau protein have been well established as neuropathological hallmarks of disease but the molecular mechanism has not been unraveled. This review focuses on the role of GSK-3β in the molecular mechanisms participating in manifestation and progression of AD.
Aims:
Our understanding of the pathological interactions between amyloidosis and tauopathy in Alzheimer's disease is incomplete. We sought to determine if the relative timing of the amyloidosis and tauopathy is critical for amyloid-enhanced tauopathy.
Methods:
We crossed an inducible tauopathy model with two β-amyloid models utilizing the doxycycline-repressible transgenic system to modulate timing and duration of human tau expression in the context of amyloidosis, and then assessed tauopathy, amyloidosis, and gliosis.
Results:
We combined inducible rTg4510 tau with APPswe/PS1dE9 [Line 85 (L85)] mice to examine the interactions between Aβ and tauopathy at different stages of amyloidosis. When we initially suppressed mutant human tau expression for 14-15 months and subsequently induced tau expression for 6 months, severe amyloidosis with robust tauopathy resulted in rTg4510/L85 but not rTg4510 mice. When we suppressed mutant tau for 7 months before inducing expression for a subsequent 6 months in another cohort of rTg4510/L85 and rTg4510 mice, only rTg4510/L85 mice displayed robust tauopathy. Lastly, we crossed rTg4510 mice to tet-regulated APPswe/ind [Line 107 (L107)] mice, using doxycycline to initially suppress both transgenes for 1 month before inducing expression for 5 months to model early amyloidosis. In contrast to rTg4510, rTg4510/L107 mice rapidly developed amyloidosis, accompanied by robust tauopathy.
Conclusions:
These data suggest that tau misfolding is exacerbated by both newly forming Aβ deposits in younger brain and mature deposits in older brains. Refined use and repurposing of these models provide new tools to explore the intersection of aging, amyloid and tauopathy, and to test interventions to disrupt the amyloid cascade.
Alzheimer’s disease comprises amyloid-β and hyperphosphorylated Tau accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms and cognitive deficits. Non-demented with Alzheimer’s disease neuropathology defines a novel clinical entity with amyloid-β and Tau pathologies but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models of non-demented with Alzheimer’s disease neuropathology are currently unavailable.
We demonstrate that J20/VLW mice (accumulating amyloid-β and hyperphosphorylated Tau) exhibit preserved hippocampal rhythmic activity and cognition, as opposed to J20 and VLW animals, which show significant alterations. Furthermore, we show that the overexpression of mutant human Tau in coexistence with amyloid-β accumulation renders a particular hyperphosphorylated Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants.
Our data highlight J20/VLW mice as a suitable animal model in which to explore the mechanisms driving cognitive preservation in non-demented with Alzheimer’s disease neuropathology. Moreover, they suggest that a differential Tau phosphorylation pattern in hippocampal interneurons prevents the loss of GABAergic septohippocampal innervation and alterations in local field potentials, thereby avoiding cognitive deficits.
Introduction
. Alzheimer’s disease models (ADMs) are currently used for drug development (DD). More than 20,000 molecules were screened for AD treatment over decades, with only one drug (Aducanumab)FDA-approved over the past 18 years. A revision of pathogenic concepts and ADMs are needed.
Areas covered
The authors discuss herein preclinical models including: (i) in vitro models (cell lines, primary neuron cell cultures, iPSC-derived brain cells), (ii) ex vivo models, and (iii) in vivo models (artificial, transgenic, non-transgenic and induced).
Expert opinion
The following types of ADMs have been reported: Mouse models (45.08%), Rat models (15.04%), Non-human Primate models (0.76%), Rabbit models (0.46%), Cat models (0.53%), Pig models (0.30%), Guinea pig models (0.15%), Octodon degu models (0.02%), Dog models (0.54%), Drosophila melanogaster models (1.79%), Zebrafish models (0.50%), Caenorhabditis elegans (1.21%), Cell culture models (3.31%), Cholinergic models (8.26%), Neurotoxic models (6.79%), Neuroinflammation models (6.92%), Neurovascular models (7.88%), and Microbiome models (0.45%).No single ADM faithfully reproduces all the pathogenic events in the human AD phenotype spectrum. ADMs should be different for (i) pathogenic studies vs basic DD, and (ii) preventive interventions vs symptomatic treatments. There cannot be an ideal ADM for DD, because AD is a spectrum of syndromes. DD can integrate pathogenic, mechanistic, metabolic, transporter and pleiotropic genes in a multisystem model.
Animal models are important experimental tools in neuroscience research since they allow appraisal of selected and specific brain pathogenesis-related questions—often not easily accessible in human patients—in a temporal and spatial pattern. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current pharmaceutical market. Of primary concern to a neuroscience researcher is the selection of the most relevant animal model to achieve pursued research goals. Researchers are challenged to develop models that recapitulate the disorder in question, but are quite often confronted with the choice between models that reproduce cardinal pathological features of the disorders caused by mechanisms that may not necessarily occur in the patients versus models that are based on known aetiological mechanisms that may not reproduce all clinical features. Besides offering some general concepts concerning the relevance, validity and generalisation of animal models for brain disorders, this chapter focuses in detail on animal models of brain disease, in particular schizophrenia models as examples of animal models of psychiatric disorders and Alzheimer’s disease models as examples of animal models of neurological/neurodegenerative disorders.
The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic
factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result
in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders
(e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins,
in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies
are here presented and discussed.
The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.
Complex diseases (e.g., Alzheimer's disease) or infectious diseases are usually caused by complicated and varied factors, including environmental and genetic factors. Multi-target (polypharmacology) drugs have been suggested and have emerged as powerful and promising alternative paradigms in modern medicinal chemistry for the development of versatile chemotherapeutic agents to solve these medical challenges. The multifunctional agents capable of modulating multiple biological targets simultaneously display great advantages of higher efficacy, improved safety profile, and simpler administration compared to single-targeted agents. Therefore, multifunctional agents would certainly open novel avenues to rationally design the next generation of more effective but less toxic therapeutic agents. Herein, the authors review the recent progress made in the discovery and design processes of selective multi-targeted agents, especially the successful application of multi-target drugs for the treatment of Alzheimer's disease.
The neuropathological correlates of Alzheimer's disease (AD) include amyloid-β (Aβ) plaques and neurofibrillary tangles. To study the interaction between Aβ and tau and their effect on synaptic function, we derived a triple-transgenic model (3×Tg-AD) harboring PS1M146V, APPSwe, and tauP301L transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1M146V knockin mice, generating mice with the same genetic background. 3×Tg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Aβ. These studies suggest a novel pathogenic role for intraneuronal Aβ with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Aβ, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
Specific antibodies and cytochemical markers combined with several imaging and morphometric techniques were used to characterize the endosomal-lysosomal system in mature neurons of the normal human central nervous system and to quantitate changes in its function in Alzheimer's disease. Compartments containing cathespin D (Cat D) and other acid hydrolases included a major subpopulation of mature lysosomes lacking mannose-6-phosphate receptors (MPR) and smaller populations of late endosomes (MPR-positive) and lipofuscin granules (MPR-negative). Antibodies to the pro-isoform of Cat D decorated perinuclear vacuolar compartments corresponding to late endosomes. Neurons and glia contained lysosomes with differing complements of acid hydrolases, implying different processing capabilities. Endosome/lysosome number per unit volume of cytoplasm was relatively well conserved within populations of normal neurons. By contrast, in morphometric analyses of Alzheimer's disease brains, 80-93% of pyramidal cells in the prefrontal cortex (laminae III or V) and hippocampus (CA2, CA3) displayed two- to eightfold higher numbers of hydrolase-positive vacuolar compartments than did corresponding cell populations in age-matched normal brains. Only 5-10% of cerebellar Purkinje cells, a less vulnerable population, showed the same statistically significant elevations. Most affected in these brain regions and in subcortical areas seemed otherwise normal by conventional histological staining and ultrastructural inspection. That both lysosomal and pro-Cat D- and MPR-positive endosomal compartments increased in number demonstrates that the endosomal-lysosomal system is activated markedly in vulnerable neuronal populations of Alzheimer's disease brains and implies that endocytosis or autophagy or both are accelerated persistently at an early stage of cellular compromise, greatly surpassing the degree of activity associated with normal aging. Early activation of the endosomal-lysosomal system represents a biological event potentially linking major etiological factors in Alzheimer's disease, including defective membrane proteins, apolipoprotein E function, and altered amyloid precursor protein processing.
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a
Lys670 → Asn, Met671 → Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment
by 9 to 10 months of age. A fivefold increase in Aβ(1–40) and a 14-fold increase in Aβ(1–42/43) accompanied the appearance
of these behavioral deficits. Numerous Aβ plaques that stained with Congo red dye were present in cortical and limbic structures
of mice with elevated amounts of Aβ. The correlative appearance of behavioral, biochemical, and pathological abnormalities
reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and
neurobiology of this disease.
JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance,
were crossed with Tg2576 transgenic mice expressing mutant β-amyloid precursor protein (APP), thus modulating the APP-Aβ (β-amyloid
peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Aβ deposits at
the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially
enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Aβ influences the formation
of neurofibrillary tangles. The interaction between Aβ and tau pathologies in these mice supports the hypothesis that a similar
interaction occurs in Alzheimer's disease.
Behavioral tests have become important tools for the analysis of functional effects of induced mutations in transgenic mice. However, depending on the type of mutation and several experimental parameters, false positive or negative findings may be obtained. Given the fact that molecular neurobiologists now make increasing use of behavioral paradigms in their research, it is imperative to revisit such problems. In this review three tests, T-maze spontaneous alternation task (T-CAT), Context dependent fear conditioning (CDFC), and Morris water maze (MWM) sensitive to hippocampal function, serve as illustrative examples for the potential problems. Spontaneous alternation tests are sometimes flawed because the handling procedure makes the test dependent on fear rather than exploratory behavior leading to altered alternation rates independent of hippocampal function. CDFC can provide misleading results because the context test, assumed to be a configural task dependent on the hippocampus, may have a significant elemental, i.e. cued, component. MWM may pose problems if its visible platform task is disproportionately easier for the subjects to solve than the hidden platform task, if the order of administration of visible and hidden platform tasks is not counterbalanced, or if inappropriate parameters are measured. Without attempting to be exhaustive, this review discusses such experimental problems and gives examples on how to avoid them.
The agents that are available at present for the management of Alzheimer's disease treat only the symptoms of neurodegeneration and, at best, result in modest, short-term improvements in cognitive function. Immunotherapy represents one of the first tests of the amyloid hypothesis in the clinic, and is an evolving approach to the treatment of Alzheimer's disease that offers a genuine opportunity to modify disease progression. Although initial clinical trials of one approach met with some setbacks, active or passive immunization holds great potential for treating or even preventing Alzheimer's disease.
Transgenic mice carrying both the human amyloid precursor protein (APP) with the Swedish mutation and the presenilin-1 A246E mutation (APP/PS1 mice) develop Alzheimer's disease-like amyloidbeta protein (Abeta) deposits around 9 months of age. These mice show an age-dependent increase in the level of Abeta40 and Abeta42 and in the number of amyloid plaques in the brain. Abeta40 and Abeta42 levels were measured, and amyloid burden and plaque number were quantified, in the hippocampus at the age of 4, 12, and 17 months in both male and female APP/PS1 mice. In all mice, amyloid burden and plaque number increased markedly with age, with female mice bearing a heavier amyloid burden and higher plaque number compared to male mice of the same age, both at 12 and at 17 months of age. The level of both Abeta40 and Abeta42 significantly increased in female mice with age and was always significantly higher in female than in male mice of the same age. Further, there were significant correlations between amyloid burden and Abeta42 level in female mice and between amyloid burden and plaques in both female and male mice. Together these data show that female APP/PS1 mice accumulate amyloid at an earlier age and that they build up more amyloid deposits in the hippocampus than age-matched male mice. Together, these results provide new insights in the potential mechanisms of the observed gender differences in the pathogenesis of AD.
Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).
Most textbooks on neurodegenerative disorders have used a classification scheme based upon either the clinical syndromes or the anatomical distribution of pathology. In contrast, this book takes a different approach by using a classification based upon molecular mechanisms, rather than clinical or anatomical boundaries. Major advances in molecular genetics and the application of biochemical and immunocytochemical techniques to neurodegenerative disorders have generated this new approach. Throughout most of the current volume, diseases are clustered according to the proteins that accumulate within cells or in the extracellular compartments or according to a shared pathogenetic mechanism, such as trinucleotide repeats that are a feature of specific genetic disorders.
Transgenic mice (Tg2576) overexpressing human β-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer’s disease-like amyloid β protein (Aβ) deposits by 8 to 10 months of age. These mice show elevated levels of Aβ40 and Aβ42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased markedly after the age of 12 months. At 15 and 19 months of age, senile plaque load was significantly greater in females than in males; in 91 mice studied at 15 months of age, the area occupied by plaques in female Tg2576 mice was nearly three times that of males. By enzyme-linked immunosorbent assay, female mice also had more Aβ40 and Aβ42 in the brain than did males, although this difference was less pronounced than the difference in histological plaque load. These data show that senescent female Tg2576 mice deposit more amyloid in the brain than do male mice, and may provide an animal model in which the influence of sex differences on cerebral amyloid pathology can be evaluated.
The recent availability of transgenic mouse models of Alzheimer disease has allowed direct in vivo assessment of the molecular and neuropathological effects of cerebral amyloid deposition. We examined 16-month-old Tg(HuAPP695. K670N-M671L)2576 mice expressing human APP K670N-M671L (APPSw), which have amyloid deposition and behavioral deficits by 11 months of age. Transgene expression is predominantly neuronal, and results in amyloid deposits, comparable to human senile plaques, at terminal zones of transgene positive neurons in cortical and limbic regions. Amyloid deposits were associated with prominent gliosis and neuritic dystrophy, without neuronal loss in CAI, loss of synaptophysin immunoreactivity in the hippocampal dentate gyrus, or loss of messenger RNA for neuronal synaptic, cytoskeletal, or metabolic proteins. We conclude that A[beta] is not acutely neurotoxic, but can disrupt neuronal processes and provoke an inflammatory response.
What causes Alzheimer's disease? Selkoe's Perspective reviews recent research identifying four different genetic causes of
Alzheimer's disease and suggests that all four point toward the deposition of amyloid beta in the brain as the initial trigger
for the disease.
Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop β-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im-munization with amyloid β peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid-β peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation- with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Aβ42and Aβ40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1:SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and β-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28α/β inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro-teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from β-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-β peptide immunization
The total numbers of neurons in five subdivisions of human hippocampi were estimated using unbiased Stereological principles and systematic sampling techniques. The method addresses the problems associated with the results and conclusions of previous quantitative studies, virtually all of which have been based on biased estimates of neuron densities. For each subdivision, the total number of neurons was calculated as the product of the estimate of the volume of the neuron‐containing layers and the estimate of the numerical density of neurons in the layers.
Each hippocampus was cut into 3‐mm‐thick slabs, transverse to the rostrocaudal axis. One 70‐μUm‐thick section from each slab was used in the analysis. The volumes of the layers containing neurons in five major subdivisions of the hippocampus (granule cell layer, hilus, CA3–2, CA1, and subiculum) were estimated with point‐counting techniques after delineation of the layers on each section. The numerical densities of neurons in each subdivision were estimated on the same sections with optical directors. The sampling used in both estimates was performed systematically in all three dimensions.
In an example of five hippocampi, the mean numbers of neurons ( CV = SD / mean ) in the different subdivisions were as follows: granule cells 15 × 10 ⁶ (0.28), hilus 2.0 × 10 ⁶ (0.16), CA3‐2 2.7 × 10 ⁶ (0.22), CA1 16 × 10 ⁶ (0.32), subiculum 4.5 × 10 ⁶ (0.19). The stereological measurements contributed approximately 25% of the observed variance. Among the five subjects there was a significant inverse relationship between age (which ranged from 47 to 85 years) and the total number of neurons in CA1 (which ranged from 24 to 11 × 10 ⁶ ).
An optimized sampling scheme for studies of the number of neurons in the human hippocampus has been designed on the basis of an analysis of variance of the estimates at different levels of the sampling scheme. Counting neurons in the five subdivisions of the human hippocampus with the optimized sampling scheme takes less than 4 hours.
Antibodies to the lysosomal hydrolases, cathepsins B and D and beta-hexosaminidase A, revealed alterations of the endosomal-lysosomal system in neurons of the Alzheimer disease brain, which preceded evident degenerative changes and became marked as atrophy, neurofibrillary pathology, or chromatolysis developed. At the earliest stages of cell atrophy, hydrolase-positive lysosomes accumulated at the basal pole and then massively throughout the perikarya and proximal and proximal dendrites of affected pyramidal neurons in Alzheimer prefrontal cortex and hippocampus, far exceeding the changes of normal aging. Secondary lysosomes as well as tertiary residual bodies (lysosomes/lipofuscin) increased implying stimulated, autophagocytosis and lysosomal system activation. Less affected brain regions, such as the thalamus, displayed similar though less extensive alterations. Certain thalamic neurons exhibited a distinctive lysosome-related abnormality characterized by the presence of cell surface blebs of varying size and number filled with intense hydrolase immunoreactivity. At more advanced stages of degeneration in still intact neurons, hydrolase-positive lipofuscin, particularly in the form of abnormally large aggregates, nearly filled the cytoplasm. Similar lipofuscin aggregates were observed in abundance in the extracellular space following cell lysis and were usually associated with deposits of the beta-amyloid protein. Degenerating neurons and their processes were the major source of these aggregates within senile plaques which contained high concentrations of acid hydrolases. We have shown in previous studies that these lysosomal hydrolases in plaques are enzymatically-active. The persistence of lysosomal structures in the brain parenchyma after neurons have degenerated is a striking and potentially diagnostic feature of Alzheimer disease which has not been observed, to our knowledge, in other degenerative diseases. The lysosomal response in degenerating Alzheimer neurons represents a probable link between an early activation of the lysosomal system in at-risk, normal-appearing neurons and the end-stage contribution of lysosomes to senile plaque formation and emphasizes a slowly progressive disturbance of the lysosomal system throughout the development of Alzheimer disease.
Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is associated with a high likelihood of developing Alzheimer's disease (AD). The pathophysiologic basis of this genetic influence is unknown. We reasoned that understanding the influence of apoE epsilon 4 on the clinical course and neuropathological features of AD may provide tests of potential mechanisms. We carried out a prospective longitudinal study to compare the age of onset, duration, and rate of progression of 359 AD patients to apoE genotype. Thirty-one of the individuals who died during the study were available for quantitative neuropathological evaluation. Statistically unbiased stereological counts of neurofibrillary tangles (NFTs) and A beta deposits were assessed in a high-order association cortex, the superior temporal sulcus. Analysis of clinical parameters compared with apoE genotype showed that the epsilon 4 allele is associated with an earlier age of onset but no change in rate of progression of dementia. Quantitative neuropathological assessment revealed that NFTs were strongly associated with clinical measures of dementia duration and severity but not with apoE genotype. A beta deposition, by contrast, was not related to clinical features but was elevated in association with apoE epsilon 4. These results indicate that apoE epsilon 4 is associated with selective clinical and neuropathological features of AD and support hypotheses that focus on an influence of apoE epsilon 4 on amyloid deposition.
β-Amyloid plaques and neurofibrillary tangles (NFTs) are the defining neuropathological hallmarks of Alzheimer's disease,
but their pathophysiological relation is unclear. Injection of β-amyloid Aβ42 fibrils into the brains of P301L mutant tau transgenic mice caused fivefold increases in the numbers of NFTs in cell bodies
within the amygdala from where neurons project to the injection sites. Gallyas silver impregnation identified NFTs that contained
tau phosphorylated at serine 212/threonine 214 and serine 422. NFTs were composed of twisted filaments and occurred in 6-month-old
mice as early as 18 days after Aβ42injections. Our data support the hypothesis that Aβ42 fibrils can accelerate NFT formation in vivo.
The tauopathies, which include Alzheimer's disease (AD) and frontotemporal dementias, are a group of neurodegenerative disorders characterized by filamentous Tau aggregates. That Tau dysfunction can cause neurodegeneration is indicated by pathogenic tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To investigate how Tau alterations provoke neurodegeneration we generated transgenic mice expressing human Tau with four tubulin-binding repeats (increased by FTDP-17 splice donor mutations) and three FTDP-17 missense mutations: G272V, P301L, and R406W. Ultrastructural analysis of mutant Tau-positive neurons revealed a pretangle appearance, with filaments of Tau and increased numbers of lysosomes displaying aberrant morphology similar to those found in AD. Lysosomal alterations were confirmed by activity analysis of the marker acid phosphatase, which was increased in both transgenic mice and transfected neuroblastoma cells. Our results show that Tau modifications can provoke lysosomal aberrations and suggest that this may be a cause of neurodegeneration in tauopathies.
It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused
by deposition of amyloid ??-peptide (A??) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of A??
in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary
tangles containing tau protein, is proposed to result from an imbalance between A?? production and A?? clearance.
Alpha-synuclein is a major component of Lewy bodies (LBs) in the substantia nigra and cortex in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and in glial inclusions in multiple systems atrophy (MSA). Mutations in alpha-synuclein have been associated with autosomal dominant forms of PD. We investigated the clinical and neuropathological effects of overexpression of human alpha-synuclein, alpha-synuclein A30P, and alpha-synuclein A53T under the control of the hamster prion protein (PrP) promoter; 5-15x endogenous levels of protein expression were achieved with widespread neuronal, including nigral, transgene expression. High expression of alpha-synuclein A30P in the Tg5093 line was associated with a progressive motor disorder with rigidity, dystonia, gait impairment, and tremor. Histological analysis of this line showed aberrant expression of the protein in cell soma and progressive CNS gliosis, but no discrete Lewy body-like alpha-synuclein inclusions could be identified. Biochemical analysis demonstrated alpha-synuclein fragmentation. Despite strong expression of the transgene in the nigra, there was no specific deterioration of the nigrostriatal dopaminergic system as assessed by quantitation of nigral tyrosine hydroxylase (TH) containing neurons, striatal TH immunoreactivity, dopamine levels, or dopamine receptor number and function. Lower expressing lines had no specific behavioral or histopathological phenotype. Thus, high expression of mutant human alpha-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line.
A double transgenic mouse expressing the amyloid precursor protein, bearing the Swedish mutations, and expressing tau protein containing three of the mutations present in frontotemporal dementia linked to chromosome 17 (FTDP-17), has been characterized. In the double transgenic mouse an increase in tau phosphorylation at serine S262 and S422 was observed compared with that found in simple transgenic mice. The phosphorylation at S262 was also found, in a much lower level, in the single transgenic mouse expressing amyloid precursor protein (APP), and it was absent in that overexpressing tau variant. Additionally, in the double transgenic mouse a slight increase in the amount of sarkosyl insoluble tau polymers was observed in comparison with that found in single transgenic tau mouse. Also, wider tau filaments were found in the double transgenic mouse compared with those found in the single transgenic mouse. Our results suggest that beta-amyloid peptide could facilitate the phosphorylation of tau at a site not directed by proline, such as serine 262, and that modification could facilitate tau aberrant aggregation. Also, they suggest that different types of tau filamentous polymers can occur in different mouse models for tauopathies, like those used for Alzheimer's disease or FTDP-17.
The relationship between senile plaques and neurofibrillary tangles, the main pathologic lesions of Alzheimer's disease, is not completely understood. We addressed this issue examining the type and amount of amyloid beta-protein (Abeta) associated with the soluble and insoluble tissue fractions in the frontal cortex of 8 cases with frontotemporal dementia with parkinsonism caused by mutations of the Tau gene (FTDP-17), in which the intracellular accumulation of polymerised tau is definitely the primary cause of neurodegeneration. As control, we examined 7 cases with frontotemporal dementia lacking distinctive histopathology (DLDH) as well as 8 pathologically normal subjects. In all cases the presence of Abeta deposits was ruled out using immunocytochemistry on sections adjacent to those used for biochemical analysis. ELISA analysis showed a 2.7 and 2.1 fold (p < 0.01) increase of soluble Abeta42 and Abeta40 in FTDP-17, compared to normal and DLDH brains, both of which had comparable levels of Abeta species. Furthermore, the immunoreactivity of the intracellular Abeta42 was significantly increased in cortical neurons of subjects affected with FTDP-17. The results demonstrate that the aggregation of tau protein produces an accumulation of Abeta, which, however, does not reach the critical concentration needed for Abetaplaques formation.
Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD4+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta42 and Abeta40, in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28a/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.
Alzheimer's disease: the amyloid cascade hypothesis
- Hardy