Intracellular Accumulation of Amyloid-Beta – A Predictor for Synaptic Dysfunction and Neuron Loss in Alzheimer's Disease

Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Göttingen Göttingen, Germany.
Frontiers in Aging Neuroscience (Impact Factor: 4). 03/2010; 2:8. DOI: 10.3389/fnagi.2010.00008
Source: PubMed


Despite of long-standing evidence that beta-amyloid (Abeta) peptides have detrimental effects on synaptic function, the relationship between Abeta, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Abeta peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer's disease (AD) which have been proven to be valuable model systems in modern AD research. The present review discusses the impact of intraneuronal Abeta accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

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Available from: Thomas A Bayer, Oct 14, 2015
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    • "In contrast, α-secretase cleaves APP within the Aβ domain, precluding the generation of Aβ in normal APP metabolism. While extracellular Aβ aggregation has long been considered as a key culprit in AD onset, intracellular Aβ accumulation is detected in neurons prior to the appearance of extracellular deposits (Wirths et al., 2001; Youmans et al., 2012) and is associated with cytotoxicity, dysfunction of organelles, and neurodegeneration (Bayer and Wirths, 2010). While the rare autosomal dominant familial AD is mostly due to overproduction of Aβ (O'Brien and Wong, 2011) or enhancing Aβ protofibril formation, far more common is the late-onset sporadic AD (sAD), thought to be caused, in part, by decreased clearance of the Aβ peptide from the CNS (Dorfman et al., 2010; Mawuenyega et al., 2010; Silverberg et al., 2010a). "
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    ABSTRACT: Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Ab) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer’s disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: b-amyloid (Ab) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Ab in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Ab42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Ab transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Ab burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Ab) and diminished secretion of TTR (less neuroprotection against cortical Ab toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.
    Frontiers in Cellular Neuroscience 02/2015; 9(17). DOI:10.3389/fncel.2015.00017 · 4.29 Impact Factor
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    • "plaques (Selkoe 2011). Smaller, oligomeric species of Aβ have proven to be neurotoxic and cause synaptic dysfunction (Shankar et al. 2008; Bayer and Wirths 2010). "
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    • "Intraneuronal Aβ is a major risk factor in AD pathology triggering neuron loss [37-40]. During the last years, intraneuronal accumulation has been reported in several mouse models including APPSDLPS1M146L[41], APPSLPS1M146L[42], Tg2576 [43], 3xTg-AD [19], APPArc[44,45], 5XFAD [21], APPT714I[46], APPSL/PS1M146L[47], APP/PS1KI [20,48,49], TBA2 mice expressing pyroglutamate modified Aβ3–42[50] and in Tg4-42 expressing Aβ4–42[23]. "
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    ABSTRACT: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptide (Abeta) within neurons. Additionally to full-length peptides, a great diversity of N-truncated Abeta variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that Abetax-42 isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and Abetax-42 species have been pointed as crucial players in AD etiology, the Abeta5-x isoforms have not received much attention. The present study is the first to show immunohistochemical evidence of Abeta5-x in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe Abeta5-x peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of Abeta5-x distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular Abeta deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal Abeta5-x. Different degrees of Abeta5-x accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular Abeta5-x, these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher Abeta5-x-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving Abeta5-x peptides and operating in a divergent way in the late and early onset forms of the disease.
    Molecular Neurodegeneration 04/2014; 9(1):13. DOI:10.1186/1750-1326-9-13 · 6.56 Impact Factor
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