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Impairments of neural circuit function in Alzheimer's disease

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Impairments of neural circuit function in Alzheimer's disease

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Abstract

An essential feature of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. We suggest that during this very extended early phase of the disease, soluble Aβ oligomers and amyloid plaques alter the function of local neuronal circuits and large-scale networks by disrupting the balance of synaptic excitation and inhibition ( E / I balance) in the brain. The analysis of mouse models of AD revealed that an Aβ-induced change of the E / I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Aβ accumulation. Therapeutics that correct the E / I balance in early AD may prevent neuronal dysfunction, widespread cell loss and cognitive impairments associated with later stages of the disease. This article is part of the themed issue ‘Evolution brings Ca ²⁺ and ATP together to control life and death’.

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... Nonetheless, the vast majority of cases of neurodegenerative diseases do not have a clear familial history; they are thought to be sporadic, whereby aging represents a major risk factor (Erkkinen et al., 2018;Hou et al., 2019). Although developmental defects could underlie the onset of sporadic cases, a large body of evidence suggests that imbalanced neuronal activity leads to loss of neuronal resilience and triggers neurodegeneration (Palop et al., 2007;Busche and Konnerth, 2016;Palop and Mucke, 2016;Arendt et al., 2017;Keogh et al., 2018;Sosulina et al., 2021). ...
... Thus, they represent a good system to investigate how this resilience is no longer sufficient to guarantee axon maintenance. Further, imbalanced activity represents a potential trigger of neurodegeneration (Palop et al., 2007;Busche and Konnerth, 2016;Palop and Mucke, 2016;Sosulina et al., 2021). Neuronal hyperactivity has been detected in patients with mild cognitive impairment, a prodromal stage of AD, and in carriers of the APOE4 allele, the most important genetic risk factor for late-onset sporadic AD, as well as in many transgenic AD mice (Hector and Brouillette, 2020). ...
... Neuronal hyperactivity has been detected in patients with mild cognitive impairment, a prodromal stage of AD, and in carriers of the APOE4 allele, the most important genetic risk factor for late-onset sporadic AD, as well as in many transgenic AD mice (Hector and Brouillette, 2020). Furthermore, activity imbalance at the circuit level is reported in AD and in AD model systems and is considered a potential trigger of neurodegeneration (Palop et al., 2007;Busche and Konnerth, 2016;Palop and Mucke, 2016;Sosulina et al., 2021). Although more specific experiments will be required, our present data suggest that an unbalanced level of activity within the local microcircuit at the PRC output synapses is at the core of the transition toward initiation of axonal degeneration in this system. ...
Article
In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult female flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered a role of postsynaptic partners of R7 to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular and circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities.SIGNIFICANCE STATEMENT:Neurons can be active and functional for several years. In the course of ageing and in disease conditions leading to neurodegeneration, subsets of neurons lose their resilience and start dying. What initiates this turning point at the cellular level is not clear. Here, we developed a model allowing to systematically describe this phase. The loss of synapses and axons represents an early and functionally relevant event towards degeneration. Utilizing the ordered distribution of Drosophila photoreceptors axon terminals, we assembled a system to study sporadic initiation of axon loss and delineated a role for non-cell-autonomous activity regulation in the initiation of axon degeneration. This work will help shedding light on key steps in the etiology of non-familial cases of neurodegenerative diseases.
... Human neuronal activity in Alzheimer's disease (AD) is characterized by a gradual, diffuse slowing of cortical oscillatory activity as the disease progresses, as can be assessed with scalp electroencephalography (EEG). There is an early increase in slow activity in the theta band (4)(5)(6)(7)(8), followed by decreases in the faster beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and alpha (8)(9)(10)(11)(12)(13) bands, and ultimately an increase in slow delta activity (0.5-4 Hz). The dominant posterior rhythm, often referred as "alpha rhythm", which is centered around ± 10 Hz in healthy adults, can slow down to below 8 Hz [1,2]. ...
... Relating information from animal models to knowledge from human studies can be challenging, for example due to many human studies being done on sporadic instead of familial AD, but doing so may give us a more complete picture of the present pathological processes, as there appears to be a general consensus that neuronal hyperexcitability plays a role [8]. Even before extensive synapse and neuron loss occurs, these pathological processes lead to altered behavioral repertoires of those neurons, and their combined effects are presumed to trigger a further detrimental cascade of neuronal excitation/inhibition imbalance with excitotoxic neurodegeneration, neuronal circuit malfunction, synchronization failure between larger neuronal assemblies, oscillatory changes, and ultimately long-distance functional and structural brain network disruption, resulting in cognitive decline [8][9][10][11][12][13][14]. So, while neuronal dysfunction is not confined to the hippocampus, it is recognized as an early AD hotspot. ...
... Besides expected changes, a deviating pattern could also be discerned: that of spectral power enhancement in the MCI group in the alpha range (8)(9)(10)(11)(12)(13). The higher alpha power (relative and absolute) values in MCI compared to SCD and AD were seen in many cortical regions but were most pronounced in the hippocampus. ...
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Background: In Alzheimer's disease (AD), oscillatory activity of the human brain slows down. However, oscillatory slowing varies between individuals, particularly in prodromal AD. Cortical oscillatory changes have shown suboptimal accuracy as diagnostic markers. We speculated that focusing on the hippocampus might prove more successful, particularly using magnetoencephalography (MEG) for capturing subcortical oscillatory activity. Objective: We explored MEG-based detection of hippocampal oscillatory abnormalities in prodromal AD patients. Methods: We acquired resting-state MEG data of 18 AD dementia patients, 18 amyloid-β-positive amnestic mild cognitive impairment (MCI, prodromal AD) patients, and 18 amyloid-β-negative persons with subjective cognitive decline (SCD). Oscillatory activity in 78 cortical regions and both hippocampi was reconstructed using beamforming. Between-group and hippocampal-cortical differences in spectral power were assessed. Classification accuracy was explored using ROC curves. Results: The MCI group showed intermediate power values between SCD and AD, except for the alpha range, where it was higher than both (p < 0.05 and p < 0.001). The largest differences between MCI and SCD were in the theta band, with higher power in MCI (p < 0.01). The hippocampi showed several unique group differences, such as higher power in the higher alpha band in MCI compared to SCD (p < 0.05). Classification accuracy (MCI versus SCD) was best for absolute theta band power in the right hippocampus (AUC = 0.87). Conclusion: In this MEG study, we detected oscillatory abnormalities of the hippocampi in prodromal AD patients. Moreover, hippocampus-based classification performed better than cortex-based classification. We conclude that a focus on hippocampal MEG may improve early detection of AD-related neuronal dysfunction.
... Recent evidence points to small, soluble misfolded oligomers, precursors of fibrillar aggregates, as major culprits in neurodegeneration (Haass and Selkoe, 2007;Busche and Konnerth, 2016;Soto and Pritzkow, 2018). Attempting to understand what initiates neurodegeneration, we hypothesized that sequestration of the buffering capacity of the proteostatic network by an excess of misfolded proteins suffices to disrupt synaptic homeostasis. ...
... Thus, in patients at high risk for developing AD, functional deficits characterized by abnormal activation and deactivation of specific networks can be detected decades before the predicted onset of clinical disease or even pathological changes (Mondadori et al., 2006). Both in mouse models of AD and human AD, neuronal hyperexcitability frequently occurs and includes epileptic features (Vossel et al., 2013;Busche and Konnerth, 2016;Lam et al., 2017). In D95N mice, neuronal hyperexcitation and network hyperactivity manifested at several levels (e.g., proneness to seizures, attenuation of circadian rhythmicity, and sleep fragmentation). ...
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Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca²⁺ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.
... Currently, the neural mechanisms by which AD causes memory loss and cognitive deficits remain poorly understood. However, recent imaging studies from clinical and animal models imply that neuronal dysfunction and functional disruption of neuronal circuits in the brain strongly contribute to memory deficits in AD cases (Busche and Konnerth, 2016;Frere and Slutsky, 2018). As the number of AD cases steadily increase each year and current treatments are only palliative, further understanding of AD-related neural mechanisms is needed for the development of meaningful new treatment strategies for improving memory and prolonging healthy cognitive function (Bast et al., 2017;Harris et al., 2020;Selkoe, 2002). ...
... The 3xTg-AD line reveals hippocampal spatial memory impairments at relatively earlier ages, even preceding plaque and tangle formation (Baglietto-Vargas et al., 2018;Oddo et al., 2003;Stimmell et al., 2019). We draw on a strong premise from the literature and our previous studies that memory-based behaviors rely on neural circuitry that is altered in aging and AD (Bast et al., 2017;Busche and Konnerth, 2016;Frere and Slutsky, 2018;Harris et al., 2020;Selkoe, 2002). Using in vivo miniscope imaging, we studied the neural calcium ensemble activities in hippocampal CA1 in freely behaving 3xTg-AD mice and non-transgenic controls (Non-Tg) at young (3-6.5 months old) and old (18-21 months old) ages. ...
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Alzheimer's disease (AD) causes progressive age-related defects in memory and cognitive function and has emerged as a major health and socio-economic concern in the US and worldwide. To develop effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Here we examine large-scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer's disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes (“miniscopes”) on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3–6.5 months old) and old (18–21 months old) ages. During open-field exploration, 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. Increased ages are correlated with decreased neural calcium activity rates across genotypes. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. The spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotor speed significantly modulates the amplitude of hippocampal neural calcium ensemble activities to a greater extent in 3xTg-AD mice during open field exploration. Our data offer new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model and provide strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.
... The disease is thought to be triggered by the pathological accumulation of soluble oligomers of amyloid β (Aβ; Mucke and Selkoe, 2012), which exert a variety of effects on different cell types (De Strooper and Karran, 2016). Alterations in synaptic transmission are among the earliest observed effects, and these include enhanced excitatory activity in corticohippocampal networks (Busche and Konnerth, 2016) and impaired Hebbian synaptic plasticity at glutamatergic synapses, specifically a marked attenuation of long-term potentiation (LTP) and facilitation of long term depression (LTD; Walsh et al., 2002;Hsieh et al., 2006;Shankar et al., 2008;Li et al., 2009Li et al., , 2011. Both of these phenomena precede the appearance of pathology and are considered to be the key cellular substrates of early cognitive impairment in AD. ...
... A region-specific increase in tonic excitatory activity is one of the earliest abnormalities that can be observed in both AD patients (Mondadori et al., 2006;Filippini et al., 2009;Sperling et al., 2009;Bateman et al., 2012;Reiman et al., 2012) and animal models of the disease (Busche et al., 2008(Busche et al., , 2012(Busche et al., , 2015Rudinskiy et al., 2012;Maier et al., 2014), usually preceding the emergence of overt pathology in AD patients by years (Busche and Konnerth, 2016). It appears to play a significant role in symptomatology and possibly pathogenesis, since reducing network hyperactivity pharmacologically has been shown to improve cognitive performance in patients with mild cognitive impairment (MCI), considered to be the prodromal stage of Alzheimer's (Bakker et al., 2012(Bakker et al., , 2015, and in AD model mice (Sanchez et al., 2012;Nygaard et al., 2015). ...
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Homeostatic synaptic plasticity (HSP) regulates synaptic strength both pre- and postsynaptically to ensure stability and efficient information transfer in neural networks. A number of neurological diseases have been associated with deficits in HSP, particularly diseases characterised by episodic network instability such as migraine and epilepsy. Recently, it has become apparent that HSP also plays a role in many neurodegenerative diseases. In this mini review, we present an overview of the evidence linking HSP to each of the major neurodegenerative diseases, finding that HSP changes in each disease appear to belong to one of three broad functional categories: (1) deficits in HSP at degenerating synapses that contribute to pathogenesis or progression; (2) HSP induced in a heterosynaptic or cell non-autonomous manner to support the function of networks of which the degenerating synapses or cells are part; and (3) induction of HSP within the degenerating population of synapses to preserve function and to resist the impact of synapse loss. Understanding the varied manifestations of HSP in neurodegeneration will not only aid understanding mechanisms of disease but could also inspire much-needed novel approaches to therapy.
... Similarly, evidence suggests that elevated levels of tonic inhibition in the dentate gyrus (DG), impaired synaptic plasticity as well as memory function via GAT3/4 in a 5xFAD mouse model . These findings have huge relevance in understanding the role of astrocytes in maintaining synaptic homeostasis in altered physiological states such as AD-associated synaptic hyperexcitability, a phenotype that spans from human studies to animals, and iPSC cell models (Hazra et al., 2013;Busche and Konnerth, 2016;Ghatak et al., 2019;Petrache et al., 2019). ADassociated hyperexcitability is thought to spread the disease pathology between brain subregions (Khan et al., 2014;Petrache et al., 2019). ...
... Secondly, we observed a significant physiological change in synaptic balance in the hippocampus of APP NL-F/NL-F mouse model, which showed a higher level of baseline spontaneous synaptic excitation, reduced phasic spontaneous inhibitory events, and an increased background tonic inhibition which was revealed after blocking the GAT3/4 with SNAP-5114. These observations are known collectively as AD-associated hyperexcitation, reported in this study as well as by others (Hazra et al., 2013;Busche and Konnerth, 2016;Ghatak et al., 2019). Previously, using the APP NL-F/NL-F mouse model we showed that the AD-associated synaptic imbalance initiates in the entorhinal cortex, an interface for hippocampal-cortical communication, and one of the first regions to be severely affected preceding typical AD pathology. ...
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Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APP NL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APP NL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APP NL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APP NL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for AD
... Neural circuits are the main mediators of various behaviors controlled by the brain, from simple functions to complex cognitive processes [8]. Interestingly, it is known that Aβ and tau have been progressively impaired the synapses, neuronal circuits, and neural networks in the brain with AD [9,10]. Several studies using neural tracing and radiological The hippocampal formation sends output projections to various regions, in addition to the subregions within the hippocampal formation. ...
... Several studies have suggested that a therapeutic approach to restoring the neural circuit may be effective in improving the clinical symptoms of patients with AD [10,231]. In addition, as clinical trials targeting molecular pathologies such as Aβ and tau pathology have failed one after the other, their potential as therapeutic targets of neural circuits is increasing [9,231]. Therefore, it has been strongly suggested that the recovery of impaired neural circuits can be an effective therapeutic target for the treatment of AD symptoms, including cognitive and psychiatric deficits. ...
Article
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Alzheimer’s disease (AD) is a neurodegenerative disease accompanied by cognitive and behavioral symptoms. These AD-related manifestations result from the alteration of neural circuitry by aggregated forms of amyloid-β (Aβ) and hyperphosphorylated tau, which are neurotoxic. From a neuroscience perspective, identifying neural circuits that integrate various inputs and outputs to determine behaviors can provide insight into the principles of behavior. Therefore, it is crucial to understand the alterations in the neural circuits associated with AD-related behavioral and psychological symptoms. Interestingly, it is well known that the alteration of neural circuitry is prominent in the brains of patients with AD. Here, we selected specific regions in the AD brain that are associated with AD-related behavioral and psychological symptoms, and reviewed studies of healthy and altered efferent pathways to the target regions. Moreover, we propose that specific neural circuits that are altered in the AD brain can be potential targets for AD treatment. Furthermore, we provide therapeutic implications for targeting neuronal circuits through various therapeutic approaches and the appropriate timing of treatment for AD.
... Rising levels of Ab o are associated with derangements in both neural circuit function and synaptic plasticity. Because these are thought to play an important role in pathogenesis (Busche and Konnerth, 2016;Mucke and Selkoe, 2012), it is important to understand both the underlying mechanisms and the role such disturbances might play in recruiting processes downstream in the pathogenic cascade. Aberrant enhancement of excitatory activity is one of the earliest changes observed in cortical and hippocampal circuits in patients with AD and model mice (Busche and Konnerth, 2016). ...
... Because these are thought to play an important role in pathogenesis (Busche and Konnerth, 2016;Mucke and Selkoe, 2012), it is important to understand both the underlying mechanisms and the role such disturbances might play in recruiting processes downstream in the pathogenic cascade. Aberrant enhancement of excitatory activity is one of the earliest changes observed in cortical and hippocampal circuits in patients with AD and model mice (Busche and Konnerth, 2016). Plasticity changes are another early signature of AD (Styr and Slutsky, 2018), and they include impairment of hippocampal long-term potentiation (LTP) and facilitation of long-term depression (LTD) (Hsieh et al., 2006;Li et al., 2009Li et al., , 2011Shankar et al., 2008;Walsh et al., 2002). ...
Article
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In Alzheimer’s disease, soluble oligomers of the amyloid-β peptide (Aβo) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aβo-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD). We also find that elevated glutamate release probability is required for Aβo-induced pathological hyperphosphorylation of tau, which is likewise NMDAR dependent. Finally, we show that chronic, repeated chemical or optogenetic induction of NMDAR-dependent LTD alone is sufficient to cause tau hyperphosphorylation without Aβo. Together, these results support a possible causal chain in which Aβo increases glutamate release probability, thus leading to enhanced LTD induction, which in turn drives hyperphosphorylation of tau. Our data identify a mechanistic pathway linking the two critical pathogenic proteins of AD.
... Thus, in the double transgenic mice model of AD (APP23xPS45), a study using two-photon Ca 2+ imaging to analyze brain activity demonstrated a progressive cortical hyperactivity without the shift from hyper to hypoexcitability shown in patient studies [88]. Nevertheless, another study performed in the APP23xPS45 mice suggest that in the hippocampus hyperxcitability starts early and decreases with age, while hypoactivity increases over time, as shown in clinical studies [89,90]. ...
... Some studies proposed that Aβ plaques disrupts voltage-gated ion channels responsible for maintaining neuronal membrane potential or calcium homeostasis [92]. Moreover, in animal models of AD soluble forms of Aβ produce alterations in the E/I ratio at the neuronal level and it has been proposed that this imbalance can be restored by treatment with benzodiazepines, which pharmacologically enhance GABAergic inhibition and prevent cellular hyperexcitability, thus ameliorating memory deficits [89]. It is worth mentioning that the influence of Aβ on neuronal activity is reciprocal, since the repair of the E/I balance can prevent the formation of Aβ plaques. ...
Article
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Neurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems that produce brain damage from which there is no recovery. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear to be similar, suggesting common neurodegenerative pathways. It is well known that oxidative stress and the production of reactive oxygen radicals plays a key role in neuronal cell damage. It has been proposed that this stress, among other mechanisms, could contribute to neuronal degeneration and might be one of the factors triggering the development of these pathologies. Another common feature in most neurodegenerative diseases is neuron hyperexcitability, an aberrant electrical activity. This review, focusing mainly on primary motor cortex pyramidal neurons, critically evaluates the idea that oxidative stress and inflammation may be involved in neurodegeneration via their capacity to increase membrane excitability.
... In addition, neuronal activity may differ across our experimental groups and hypothetically change RABV propagation if silent and active synapses are differentially conducive. The amyloid-loaded brains have an increased number of silent and hyperactive neurons, with the latter located in the vicinity of the plaques (61,62). Increased numbers of hyperactive neurons occur at early stages, while the balance between hyperactive and silent neurons is achieved in the 8-month-old APP/PS1 transgenic mice used here. ...
... Consequently, activity-dependent mechanisms favoring the transplanted neurons over neurons preexisting in the pathological environment may contribute to the hyperinnervation of neurons transplanted into the amyloidosis and aged environments. Again, the similar levels of hyperconnectivity observed between the transplants into amyloid-loaded brains and the normal aged brain argue against a major role of an imbalance between synaptic excitation and inhibition in the APP/PS1 mice (61). Likewise, we could not detect any differences in the number of interneurons stained for parvalbumin in V1 of the host environments ( fig. ...
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Transplantation is a clinically relevant approach for brain repair, but much remains to be understood about influences of the disease environment on transplant connectivity. To explore the effect of amyloid pathology in Alzheimer’s disease (AD) and aging, we examined graft connectivity using monosynaptic rabies virus tracing in APP/PS1 mice and in 16- to 18-month-old wild-type (WT) mice. Transplanted neurons differentiated within 4 weeks and integrated well into the host visual cortex, receiving input from the appropriate brain regions for this area. Unexpectedly, we found a prominent several-fold increase in local inputs, in both amyloid-loaded and aged environments. State-of-the-art deep proteome analysis using mass spectrometry highlights complement system activation as a common denominator of environments promoting excessive local input connectivity. These data therefore reveal the key role of the host pathology in shaping the input connectome, calling for caution in extrapolating results from one pathological condition to another.
... However, it has not yet been elucidated the origin of these network alterations. A potential hypothesis is the hyperexcitability of the cortical neurons due to the toxicity of the amyloid plaques over the inhibitory terminals [12]. This loss of the excitation/inhibition balance lead to a less flexible state of the oscillatory activity and a tendency to hypersynchronize neurophysiological signals at different frequency bands [13]. ...
... Linked to this last idea, is the other plausible interpretation of sMCI hypersynchronization as a sign of functional network disruption. Hypersynchronization, can be induced by the impaired excitatory/inhibitory balance as indicated in animal models of the disease due to the toxicity of amyloid plaques to inhibitory terminals [12,48,49]. The fact that MCI patients showed hypersynchronization (and less variability across the QRS window) as compared to the control group, reinforces this interpretation. ...
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A promising question in neuroscience is enlightening the interaction between heart and brain electrophysiological activities and its relationship with the cognitive status. Our aim here is to study the Heart-Brain Interplay (HBI) and assess whether HBI alterations can be biomarkers for Alzheimer's disease progression. To this end, we recorded resting state Magnetoencephalography (MEG) for healthy controls and two groups of Mild Cognitive Impairment (MCI) patients without cardiovascular alteration symptoms: stable and progressive to Alzheimer's disease. Our results demonstrated that MCI patients showed alterations in the HBI that can be summarized as follows: (i) heart evoked responses were interrupted in MCI and this lack of interaction correlate with cognitive performance; (ii) the influence of the heart activity onto brain networks fluctuates along cardiac cycle, being less responsive the MCI networks, and (iii) including HBI-MEG signatures in a machine learning procedure to predict AD progression outperform the results obtained using standard resting state MEG signatures. Our results highlight the role of heart in cognitive neuroscience by showing that basal brain networks are interrelated with the cardiac dynamics and propose the use of heart reference as a biomarker. The ignorance of the cardiac dynamic could be resulting in wastage of relevant information otherwise critical to understand disease as dementia.
... AD has been extensively described as a disconnection syndrome (Delbeuck et al., 2003;Engels et al., 2017;Hof, 1997), and recent data describe a more complex, nonlinear trajectory of neuropathological change (Harris et al., 2020). An increasing number of studies indicate that an increase in FC, at least as measured by EEG and MEG, is one of the first signs of neurodegeneration (Bajo et al., 2010;Bonanni et al., 2020;Busche and Konnerth, 2016;Canuet et al., 2015;López et al., 2014;Nakamura et al., 2017;Pusil et al., 2019;Ramírez-Toraño et al., 2021). Histological examination of brain tissue in AD patients has shown that the area surrounding a senile plaque is usually characterized by a lack of gamma-aminobutyric acid (GABAergic) neurons (Garcia-Marin et al., 2009). ...
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Introduction: The human brain shows modest traits of sexual dimorphism, with the female brain, on average, 10% smaller than the male brain. These differences do not imply a lowered cognitive performance, but suggest a more optimal brain organization in women. Here we evaluate the patterns of functional connectivity (FC) in women and men from the Connectomics of Brain Aging and Dementia sample. Methods: We used phase locking values to calculate FC from the magnetoencephalography time series in a sample of 138 old adults (87 females and 51 males). We compared the FC patterns between sexes, with the intention of detecting regions with different levels of connectivity. Results: We found a frontal cluster, involving anterior cingulate and the medial frontal lobe, where women showed higher FC values than men. Involved connections included the following: (1) medial parietal areas, such as posterior cingulate cortices and precunei; (2) right insula; and (3) medium cingulate and paracingulate cortices. Moreover, these differences persisted when considering only cognitively intact individuals, but not when considering only cognitively impaired individuals. Discussion: Increased anteroposterior FC has been identified as a biomarker for increased risk of developing cognitive impairment or dementia. In our study, cognitively intact women showed higher levels of FC than their male counterparts. This result suggests that neurodegenerative processes could be taking place in these women, but the changes are undetected by current diagnosis tools. FC, as measured here, might be valuable for early identification of this neurodegeneration.
... Data from structural and functional magnetic resonance imaging (MRI) (Dai and He, 2014;Prescott et al., 2014), as well as magnetoencephalopathy (MEG) (Lopez-Sanz et al., 2019) and electroencephalography Babiloni et al., 2020) all demonstrate significant changes in neural networks even prior to the onset of clinical dementia. While such changes are not explicit in the popular A/T/N (amyloid/tau/neurodegeneration) model of AD (Jack et al., 2016), they appear to be an early consequence of the accumulation of beta amyloid (Busche and Konnerth, 2016;Nakamura et al., 2017), and thus may be an early warning sign of impending neurodegeneration. Indeed, models of the natural history of AD that propose that the loss of synapses is one of the first pathological stages of AD (Selkoe, 2002), imply changes in the connectome. ...
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The natural history of Alzheimer’s Disease (AD) includes significant alterations in the human connectome, and this disconnection results in the dementia of AD. The organizing principle of our research project is the idea that the expression of cognitive dysfunction in the elderly is the result of two independent processes — the neuropathology associated with AD, and second the neuropathological changes of cerebrovascular disease. Synaptic loss, senile plaques, and neurofibrillary tangles are the functional and diagnostic hallmarks of AD, but it is the structural changes as a consequence of vascular disease that reduce brain reserve and compensation, resulting in an earlier expression of the clinical dementia syndrome. This work is being completed under the auspices of the Human Connectome Project (HCP). We have achieved an equal representation of Black individuals (vs. White individuals) and enrolled 60% Women. Each of the participants contributes demographic, behavioral and laboratory data. We acquire data relative to vascular risk, and the participants also undergo in vivo amyloid imaging, and magnetoencephalography (MEG). All of the data are publicly available under the HCP guidelines using the Connectome Coordinating Facility and the NIMH Data Archive. Locally, we use these data to address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MEG, and in vivo beta amyloid imaging.
... The mTORC1 (mechanistic target of rapamycin (mTOR) complex 1) pathway is differentially regulated in Rett syndrome and other syndromes associated with ASD [188]. In the case of AD, the abnormal accumulation of soluble Aβ results in the impairment of neural circuits and increases the number of hyperactive cells [189]. According to relevant studies, the normal level of soluble Aβ supports synaptic plasticity, while increased levels trigger a toxic cascade that results in synaptic impairment and cognitive deficits [190]. ...
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Autism spectrum disorder (ASD) and Alzheimer’s disease (AD) are neurodevelopmental and neurodegenerative disorders affecting two opposite ends of life span, i.e., childhood and old age. Both disorders pose a cumulative threat to human health, with the rate of incidences increasing considerably worldwide. In the context of recent developments, we aimed to review correlated symptoms and genetics, and overlapping aspects in the mechanisms of the pathogenesis of ASD and AD. Dementia, insomnia, and weak neuromuscular interaction, as well as communicative and cognitive impairments, are shared symptoms. A number of genes and proteins linked with both disorders have been tabulated, including MECP2, ADNP, SCN2A, NLGN, SHANK, PTEN, RELN, and FMR1. Theories about the role of neuron development, processing, connectivity, and levels of neurotransmitters in both disorders have been discussed. Based on the recent literature, the roles of FMRP (Fragile X mental retardation protein), hnRNPC (heterogeneous ribonucleoprotein-C), IRP (Iron regulatory proteins), miRNAs (MicroRNAs), and α-, β0, and γ-secretases in the posttranscriptional regulation of cellular synthesis and processing of APP (amyloid-β precursor protein) have been elaborated to describe the parallel and overlapping routes and mechanisms of ASD and AD pathogenesis. However, the interactive role of genetic and environmental factors, oxidative and metal ion stress, mutations in the associated genes, and alterations in the related cellular pathways in the development of ASD and AD needs further investigation.
... As mGlu 1 PAM development continues toward producing a clinical candidate, our study provides preclinical proof of concept that mGlu 1 PAMs rescue cognitive deficits in addition to their previously observed antipsychotic-like efficacy (Yohn et al., 2020). Based on our mechanistic work, it is possible that mGlu 1 PAMs will have broad utility in other disorders where I/E balance is perturbed such as epilepsy, autism, and Alzheimer's disease (Busche and Konnerth, 2016;Fritschy, 2008;Gao and Penzes, 2015). Altogether, these data suggest that mGlu 1 PAMs have the potential to confer breakthrough efficacy to improve the lives of patients living with schizophrenia. ...
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Evidence for prefrontal cortical (PFC) GABAergic dysfunction is one of the most consistent findings in schizophrenia and may contribute to cognitive deficits. Recent studies suggest that the mGlu1 subtype of metabotropic glutamate receptor regulates cortical inhibition; however, understanding the mechanisms through which mGlu1 positive allosteric modulators (PAMs) regulate PFC microcircuit function and cognition is essential for advancing these potential therapeutics toward the clinic. We report a series of electrophysiology, optogenetic, pharmacological magnetic resonance imaging, and animal behavior studies demonstrating that activation of mGlu1 receptors increases inhibitory transmission in the prelimbic PFC by selective excitation of somatostatin-expressing interneurons (SST-INs). An mGlu1 PAM reverses cortical hyperactivity and concomitant cognitive deficits induced by N-methyl-d-aspartate (NMDA) receptor antagonists. Using in vivo optogenetics, we show that prelimbic SST-INs are necessary for mGlu1 PAM efficacy. Collectively, these findings suggest that mGlu1 PAMs could reverse cortical GABAergic deficits and exhibit efficacy in treating cognitive dysfunction in schizophrenia.
... Amyloid plaque burden is compelling for further study because it may shape neuronal activity, which in turn can alter sensory and pain processing. In both humans (Zott et al., 2018) and animals, amyloid proximity correlates with neuronal hyperactivity (Busche, 2012;Gurevicius et al., 2013;Busche and Konnerth, 2016;Zott et al., 2019). Downstream consequences of amyloid accumulation, such as glial activation (Barger and Harmon, 1997;Pasqualetti et al., 2015;Hansen et al., 2018) or neuronal death (Klyubin, 2008;Mattson, 1997;Smale et al., 1995;Kobayashi et al., 2002;Kobayashi et al., 2005), might also shape pain perception. ...
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Pain and cognitive decline increase with age. In particular, there is a troubling relationship between dementia and pain, with some studies showing higher prevalence and inadequate treatment of pain in this population. Alzheimer’s disease (AD) is one of the most common causes of dementia in older adults. Amyloid plaques are a hallmark of AD. The downstream processes these plaques promote are believed to affect neuronal and glial health and activity. There is a need to better understand how the neuropathological changes of AD shape neural activity and pain sensitivity. Here, we use the 5XFAD mouse model, in which dense amyloid accumulations occur at early ages, and in which previous studies reported signs of cognitive decline. We hypothesized that 5XFAD mice develop sensory and pain processing dysfunctions. Although amyloid burden was high throughout the brain, including in regions involved with sensory processing, we identified no functionally significant differences in reflexive or spontaneous signs of pain. Furthermore, expected signs of cognitive decline were modest; a finding consistent with variable results in the literature. These data suggest that models recapitulating other pathological features of Alzheimer’s disease might be better suited to studying differences in pain perception in this disease.
... Brain plasticity (i.e., neuroplasticity), which is defined as the ability of the brain to adapt to experiences through the formation of new neural pathways, is primarily mediated by electrical and chemical excitation and inhibition (de Oliveira, 2020). An abnormal excitatory and inhibitory balance of neural pathways can lead to neurological disorders such as Alzheimer's and Parkinson's disease, epilepsy, and multiple sclerosis (Bonansco & Fuenzalida, 2016;Busche & Konnerth, 2016;Lindenbach & Bishop, 2013;Zhong et al., 2016). Therefore, a CNS capable of efficiently transmitting information and balancing neuronal excitation and inhibition is vital to everyday human life. ...
Article
Background: There is a growing concern among the scientific community that the effects of transcranial direct current stimulation (tDCS) are highly variable across studies. The use of different tDCS devices and electrode sizes may contribute to this variability; however, this issue has not been verified experimentally. Objective: To evaluate the effects of tDCS device and electrode size on quadriceps motor cortical excitability. Methods: The effect of tDCS device and electrode size on quadriceps motor cortical excitability was quantified across a range of TMS intensities using a novel evoked torque approach that has been previously shown to be highly reliable. In experiment 1, anodal tDCS-induced excitability changes were measured in twenty individuals using two devices (Empi and Soterix) on two separate days. In experiment 2, anodal tDCS-induced excitability changes were measured in thirty individuals divided into three groups based on the electrode size. A novel Bayesian approach was used in addition to the classical hypothesis testing during data analyses. Results: There were no significant main or interaction effects, indicating that cortical excitability did not differ between different tDCS devices or electrode sizes. The lack of pre-post time effect in both experiments indicated that cortical excitability was minimally affected by anodal tDCS. Bayesian analyses indicated that the null model was more favored than the main or the interaction effects model. Conclusions: Motor cortical excitability was not altered by anodal tDCS and did not differ by devices or electrode sizes used in the study. Future studies should examine if behavioral outcomes are different based on tDCS device or electrode size.
... It has been also described that Aβ plaques could have a toxic effect in their surrounded inhibitory and excitatory neurons [123,124], thus disrupting neuronal networks [125]. Moreover, prior to amyloid plaque formation, oligomeric A peptide causes the hyperactivity of hippocampal neurons and network hypersynchrony [126]. Furthermore, p-tau also changes the normal network functioning by depressing synapse efficiency and quantity. ...
Article
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Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. Ideally, biomarkers should also be non-invasive and cost-effective. This review aims to focus on the usefulness and limitations of electroencephalography (EEG) in the search for Alzheimer's disease (AD) biomarkers. The main aim of this article is to review the evolution of the most used biomarkers in AD and the need for new peripheral and, ideally, non-invasive biomarkers. The characteristics of the EEG as a possible source for biomarkers will be revised, highlighting its advantages compared to the molecular markers available so far.
... While decreased synaptic inhibition is commonly observed in AD mouse models (Rocher et al., 2008;Verret et al., 2012;Hazra et al., 2013), compensatory remodeling of inhibitory circuits is thought to result from early aberrant excitation (Palop and Mucke, 2016). In support, APP23×PS45 mice have increased activity of hippocampal CA1 pyramidal neurons prior to plaque formation (Busche and Konnerth, 2016). Additionally, increased intrinsic excitability from mature dentate granule cells (DGCs) is reported in Tg2576 AD mice (Hazra et al., 2013;Nenov et al., 2015). ...
Article
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The dentate gyrus is both a critical gatekeeper for hippocampal signal processing and one of the first brain regions to become dysfunctional in Alzheimer's disease (AD). Accordingly, the appropriate balance of excitation and inhibition through the dentate is a compelling target for mechanistic investigation and therapeutic intervention in early AD. Previously, we reported an increased long-term potentiation (LTP) magnitude at medial perforant path-dentate granule cell (MPP-DGC) synapses in slices from both male and acutely ovariectomized female TgF344-AD rats compared with wild type (Wt) as early as 6 months of age that is accompanied by an increase in steady-state postsynaptic depolarization during the high-frequency stimulation used to induce plasticity. Subsequently, we found that heightened function of β-adrenergic receptors (β-ARs) drives the increase in the LTP magnitude, but the increase in steady-state depolarization was only partially due to β-AR activation. As we previously reported no detectable difference in spine density or presynaptic release probability, we entertained the possibility that DGCs themselves might have modified passive or active membrane properties, which may contribute to the significant increase in charge transfer during high-frequency stimulation. Using brain slice electrophysiology from 6-month-old female rats acutely ovariectomized to eliminate variability due to fluctuating plasma estradiol, we found significant changes in passive membrane properties and active membrane properties leading to increased DGC excitability in TgF344-AD rats. Specifically, TgF344-AD DGCs have an increased input resistance and decreased rheobase, decreased sag, and increased action potential (AP) spike accommodation. Importantly, we found that for the same amount of depolarizing current injection, DGCs from TgF344-AD compared with Wt rats have a larger magnitude voltage response, which was accompanied by a decreased delay to fire the first action potential, indicating TgF344-AD DGCs membranes are more excitable. Taken together, DGCs in TgF344-AD rats are more excitable, which likely contributes to the heightened depolarization during high-frequency synaptic activation.
... Interestingly, growing evidence suggest that blocking excessive neuronal activity could limit amyloid progression and ultimately prevent the development of AD [27]. Indeed, excessive neuronal firing increase amyloid formation [28,29] and neuronal hyperactivity has been suggested to constitute an early dysfunction in the pathophysiological cascade of AD [30], while its modulation could reduce amyloid accumulation, since a reduction in neuronal activity results in decreased amyloid production [31], as well as reduced axonal dystrophy and synaptic loss in areas near amyloid plaques [32]. Based on accumulating findings on the link between excessive neuronal activity and brain amyloid accumulation, some authors have proposed that targeting neuronal hyperactivity with pharmacological treatment such as antiepileptic drugs may attenuate amyloid progression and ultimately prevent the development of AD [27]. ...
Article
Recent evidence suggests an association between benzodiazepines (BZDs) use and lower brain amyloid load, a hallmark of AD pathophysiology. Other AD-related markers include hippocampal atrophy, but the effect of BZDs on hippocampal volume remains unclear. We aimed at 1) replicating findings on BZDs use and brain amyloid load and 2) investigating associations between BZDs use and hippocampal volume, in the MEMENTO clinical cohort of nondemented older adults with isolated memory complaint or light cognitive impairment at baseline. Total Standardized Uptake Value Ratio (SUVR) of brain amyloid load and hippocampal volume (HV) were obtained, respectively, from ¹⁸F Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI), and compared between BZD chronic users and nonusers using multiple linear regressions adjusted for age, sex, educational level, ApoE ε4 genotype, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant intake. BZD users were more likely to manifest symptoms of depression, anxiety and apathy. In the MRI subgroup, BZD users were also more frequently females with low education and greater clinical impairments as assessed with the clinical dementia rating scale. Short- versus long-acting BZDs, Z-drugs versus non-Z-drugs BZDs, as well as dose and duration of BZD use, were also considered in the analyses. Total SUVR and HV were significantly lower and larger, respectively, in BZD users (n = 38 in the PET subgroup and n = 331 in the MRI subgroup) than in nonusers (n = 251 in the PET subgroup and n = 1840 in the MRI subgroup), with a medium (Cohen’s d = −0.43) and low (Cohen’s d = 0.10) effect size, respectively. Short-acting BZDs and Z-drugs were more significantly associated with larger HV. We found no effect of dose and duration of BZD use. Our results support the involvement of the GABAergic system as a potential target for blocking AD-related pathophysiology, possibly via reduction in neuronal activity and neuroinflammation. Future longitudinal studies may confirm the causal effect of BZDs to block amyloid accumulation and hippocampal atrophy.
... Diverse studies in AD transgenic mouse models have reported pre-plaque alterations in hippocampal synaptic transmission, for instance, it has been suggested that Aβ induces changes in the excitation and inhibition equilibrium which consequently causes hyperactivity in cortical and hippocampal neurons (Busche and Konnerth, 2016). One of the first research showing impaired neural communication preceding plaques deposition was performed with APP mice carrying the Indiana mutation mice; there was a decrease in density of hippocampal presynaptic terminals and neurons which negatively impacted CA3-CA1 synaptic transmission (Hsia et al., 1999). ...
Conference Paper
Alzheimer´s disease (AD) is the most common type of dementia representing an estimated 60-80% of all cases, and no cure or successful therapy has been found. Two main hallmarks have been identified in AD histopathology: senile plaques, composed of amyloid-β protein (Aβ), and neurofibrillary tangles, composed of phosphorylated TAU protein. Additionally, genetic studies have shown that immune processes play important roles in AD. Microglial gene expression and function are closely correlated to amyloid pathology and are therefore potential targets for altering the progression of AD. Recently an Amyloid Precursor Protein knock-in line was generated, which, in contrast to transgenic AD mice shows an Aβ pathology without overexpression. This project aims to analyse if microglial cells are active modulators of Aβ plaques and synaptic changes in APP knock-in mice at the early stages of the pathology. Initial characterisation of electrophysiological phenotypes for APPNL-G-F and APPNL-F were studied. Also, dose- and time-dependent effects of the drug PLX5622, which has been shown to specifically deplete microglia, were analysed. APPNL-G-F mice exhibited unaltered synaptic transmission at 3.5 months of age regardless a clear accumulation of hippocampal Aβ plaques. APPNL-F mice showed increased glutamate release probability, unchanged spontaneous excitatory activity and little accumulation of Aβ plaques at 10 months of age. After PLX5622 treatments, surviving microglia tended to be CD68+ in both APP knock-in models. Partial microglia ablation led to aged but not young wild type animals mimicking the increased glutamate release probability and exacerbated the APP knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. It is suggested that alteration of surviving microglia towards a phagocytic phenotype, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in AD.
... These pathways were involved in different mechanisms, such as synaptic function, neuron death and blood-brain barrier. For example, axon guidance is a crucial process for neural circuit formation 77 which is an important topic in AD study since it remains unresolved why neuronal circuits become dysfunctional in response to high Aβ levels and how circuit abnormalities could be repaired 78 . Aβ and hyperphosphorylation of tau could cause synaptic damage, leading to AD, while axon-guidance molecules could regulate the balance between synapse formation and Aβ 79 . ...
Article
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Alzheimer’s disease (AD) is a neurodegenerative disease that eventually affects memory and behavior. The identification of biomarkers based on risk factors for AD provides insight into the disease since the exact cause of AD remains unknown. Several studies have proposed microRNAs (miRNAs) in blood as potential biomarkers for AD. Exposure to heavy metals is a potential risk factor for onset and development of AD. Blood cells of subjects that are exposed to lead detected in the circulatory system, potentially reflect molecular responses to this exposure that are similar to the response of neurons. In this study we analyzed blood cell-derived miRNAs derived from a general population as proxies of potentially AD-related mechanisms triggered by lead exposure. Subsequently, we analyzed these mechanisms in the brain tissue of AD subjects and controls. A total of four miRNAs were identified as lead exposure-associated with hsa-miR-3651, hsa-miR-150-5p and hsa-miR-664b-3p being negatively and hsa-miR-627 positively associated. In human brain derived from AD and AD control subjects all four miRNAs were detected. Moreover, two miRNAs (miR-3651, miR-664b-3p) showed significant differential expression in AD brains versus controls, in accordance with the change direction of lead exposure. The miRNAs’ gene targets were validated for expression in the human brain and were found enriched in AD-relevant pathways such as axon guidance. Moreover, we identified several AD relevant transcription factors such as CREB1 associated with the identified miRNAs. These findings suggest that the identified miRNAs are involved in the development of AD and might be useful in the development of new, less invasive biomarkers for monitoring of novel therapies or of processes involved in AD development.
... While it is conceivable that these exogenous αSyn PFFs were able to seed additional Aβ plaques in L85 mice, our measurements, recorded at the end stage of the disease, did not detect an obvious concentration of αSyn inclusions near Aβ deposits. It is also possible that neuronal hyperactivation resulting from, or even preceding, Aβ plaque formation in APP mouse models [85][86][87], promoted PFF neuronal uptake. Elevated neuronal activity can significantly influence neuronal αSyn cellular uptake and release [88,89]. ...
Article
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Background The misfolding of host-encoded proteins into pathological prion conformations is a defining characteristic of many neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Lewy body dementia. A current area of intense study is the way in which the pathological deposition of these proteins might influence each other, as various combinations of co-pathology between prion-capable proteins are associated with exacerbation of disease. A spectrum of pathological, genetic and biochemical evidence provides credence to the notion that amyloid β (Aβ) accumulation can induce and promote α-synuclein pathology, driving neurodegeneration. Methods To assess the interplay between α-synuclein and Aβ on protein aggregation kinetics, we crossed mice expressing human α-synuclein (M20) with APPswe/PS1dE9 transgenic mice (L85) to generate M20/L85 mice. We then injected α-synuclein preformed fibrils (PFFs) unilaterally into the hippocampus of 6-month-old mice, harvesting 2 or 4 months later. Results Immunohistochemical analysis of M20/L85 mice revealed that pre-existing Aβ plaques exacerbate the spread and deposition of induced α-synuclein pathology. This process was associated with increased neuroinflammation. Unexpectedly, the injection of α-synuclein PFFs in L85 mice enhanced the deposition of Aβ; whereas the level of Aβ deposition in M20/L85 bigenic mice, injected with α-synuclein PFFs, did not differ from that of mice injected with PBS. Conclusions These studies reveal novel and unexpected interplays between α-synuclein pathology, Aβ and neuroinflammation in mice that recapitulate the pathology of Alzheimer’s disease and Lewy body dementia.
... Early hippocampal disruptions of spontaneous excitatory signaling As dysfunctional synaptic signaling is a hallmark of AD [20], we next investigated functional neuronal signaling in acutely isolated brain slices by whole-cell patch-clamp recordings of pyramidal neurons in the cerebral cortex and the CA1 region of the hippocampus. All measured passive electrical membrane properties were unchanged, in both the cerebral cortex and hippocampus of 5xFAD mice at both 2 and 4 mo (Tables S3 and S4). ...
Article
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Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, this crucial metabolic interplay during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in the 5xFAD hippocampus. This hyperactive neuronal phenotype coincided with decreased hippocampal tricarboxylic acid (TCA) cycle metabolism mapped by stable ¹³ C isotope tracing. Particularly, reduced astrocyte TCA cycle activity and decreased glutamine synthesis led to hampered neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, the cerebral cortex of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism, which may suggest a metabolic compensation in this brain region. We found limited changes when we explored the brain proteome and metabolome of the 5xFAD mice, supporting that the functional metabolic disturbances between neurons and astrocytes are early primary events in AD pathology. In addition, synaptic mitochondrial and glycolytic function was selectively impaired in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex regional and cell-specific metabolic adaptations in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunctions in AD.
... Consequently, alterations in the local criticality of networks might lead to impaired coupling. In agreement with this idea, brain disorders such as Alzheimer's (Montez et al., 2009) and schizophrenia have been associated with alterations in criticality, excitation/inhibition (E/I) balance (Lisman, 2012;Busche and Konnerth, 2016), and reduced long-range phase coupling in fronto-parietal networks (Babiloni et al., 2004;Sheffield et al., 2015). Of note, there is considerable variation in critical brain dynamics among individuals (Linkenkaer-Hansen et al., 2007) and brain states such as focused attention (Irrmischer et al., 2018), suggesting that it is biologically relevant to understand the implications of near-critical brain dynamics and E/I balance on long-range coupling and information processing. ...
Article
Brain function depends on segregation and integration of information processing in brain networks often separated by long-range anatomic connections. Neuronal oscillations orchestrate such distributed processing through transient amplitude and phase coupling, yet surprisingly, little is known about local network properties facilitating these functional connections. Here, we test whether criticality, a dynamical state characterized by scale-free oscillations, optimizes the capacity of neuronal networks to couple through amplitude or phase, and transfer information. We coupled in silico networks which exhibit oscillations in the a band (8–16 Hz), and varied excitatory and inhibitory connectivity. We found that phase coupling of oscillations emerges at criticality, and that amplitude coupling, as well as information transfer, are maximal when networks are critical. Importantly, regulating criticality through modulation of synaptic gain showed that critical dynamics, as opposed to a static ratio of excitatory and inhibitory connections, optimize network coupling and information transfer. Our data support the idea that criticality is important for local and global information processing and may help explain why brain disorders characterized by local alterations in criticality also exhibit impaired long-range synchrony, even before degeneration of axonal connections.
... Previous work has found a hyperexcitable effect of amyloid-b on neural activity in the preclinical-to-prodromal stages of the disease in humans 33,37,81 and in non-human animal and in vitro Alzheimer's disease models that do not fully recapitulate the late-stage disease process. [82][83][84][85][86][87][88][89] This effect shifts towards hypoexcitability at later stages of Alzheimer's disease, 33,90-92 signifying synapse failure and neurodegeneration. Given that patients were required to exhibit clinically significant cognitive impairments for inclusion in our study, our findings provide further support for a shift towards a hypoexcitable effect of amyloid-b on neural activity in the later stages of Alzheimer's disease, represented here as a macro-level shift towards activity in slower frequencies. ...
Article
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An extensive electrophysiological literature has proposed a pathological ‘slowing’ of neuronal activity in patients on the Alzheimer’s disease spectrum. Supported by numerous studies reporting increases in low-frequency and decreases in high-frequency neural oscillations, this pattern has been suggested as a stable biomarker with potential clinical utility. However, no spatially resolved metric of such slowing exists, stymieing efforts to understand its relation to proteinopathy and clinical outcomes. Further, the assumption that this slowing is occurring in spatially overlapping populations of neurons has not been empirically validated. In the current study, we collected cross-sectional resting state measures of neuronal activity using magnetoencephalography from 38 biomarker-confirmed patients on the Alzheimer’s disease spectrum and 20 cognitively normal biomarker-negative older adults. From these data, we compute and validate a new metric of spatially resolved oscillatory deviations from healthy ageing for each patient on the Alzheimer’s disease spectrum. Using this Pathological Oscillatory Slowing Index, we show that patients on the Alzheimer’s disease spectrum exhibit robust neuronal slowing across a network of temporal, parietal, cerebellar and prefrontal cortices. This slowing effect is shown to be directly relevant to clinical outcomes, as oscillatory slowing in temporal and parietal cortices significantly predicted both general (i.e. Montreal Cognitive Assessment scores) and domain-specific (i.e. attention, language and processing speed) cognitive function. Further, regional amyloid-β accumulation, as measured by quantitative 18F florbetapir PET, robustly predicted the magnitude of this pathological neural slowing effect, and the strength of this relationship between amyloid-β burden and neural slowing also predicted attentional impairments across patients. These findings provide empirical support for a spatially overlapping effect of oscillatory neural slowing in biomarker-confirmed patients on the Alzheimer’s disease spectrum, and link this effect to both regional proteinopathy and cognitive outcomes in a spatially resolved manner. The Pathological Oscillatory Slowing Index also represents a novel metric that is of potentially high utility across a number of clinical neuroimaging applications, as oscillatory slowing has also been extensively documented in other patient populations, most notably Parkinson’s disease, with divergent spectral and spatial features.
... Several human brain disorders, including neurodegeneration diseases such as Alzheimer's (Busche and Konnerth, 2016;Canter et al., 2016;Zott et al., 2018), Huntington's (Miller and Bezprozvanny, 2010;Miller et al., 2011;Ghiglieri et al., 2019;Blumenstock and Dudanova, 2020) and Parkinson's diseases (Caligiore et al., 2016;McGregor and Nelson, 2019), have to some extent been attributed to dysfunctions in neural circuitries. Progressive neuronal cell death is thought to be linked in part to abnormal cell-cell communication between subpopulations of neurons in the brain, seen as alterations in synaptic function as well as disrupted intracellular signaling. ...
Article
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The human brain contains a wide array of billions of neurons and interconnections, which are often simplified for analysis in vitro using compartmentalized microfluidic devices for neuronal cell culturing, to better understand neuronal development and disease. However, such devices are traditionally incompatible for high-pressure freezing and high-resolution nanoscale imaging and analysis of their sub-cellular processes by methods including electron microscopy. Here we develop a novel compartmentalized neuronal co-culture platform allowing reconstruction of neuronal networks with high variable spatial control, which is uniquely compatible for high-pressure freezing. This cryo-fixation method is well-established to enable high-fidelity preservation of the reconstructed neuronal networks and their sub-cellular processes in a near-native vitreous state without requiring chemical fixatives. To direct the outgrowth of neurites originating from two distinct groups of neurons growing in the two different compartments, polymer microstructures akin to microchannels are fabricated atop of sapphire disks. Two populations of neurons expressing either enhanced green fluorescent protein (EGFP) or mCherry were grown in either compartment, facilitating the analysis of the specific interactions between the two separate groups of cells. Neuronally differentiated PC12 cells, murine hippocampal and striatal neurons were successfully used in this context. The design of this device permits direct observation of entire neuritic processes within microchannels by optical microscopy with high spatial and temporal resolution, prior to processing for high-pressure freezing and electron microscopy. Following freeze substitution, we demonstrate that it is possible to process the neuronal networks for ultrastructural imaging by electron microscopy. Several key features of the embedded neuronal networks, including mitochondria, synaptic vesicles, axonal terminals, microtubules, with well-preserved ultrastructures were observed at high resolution using focused ion beam – scanning electron microscopy (FIB-SEM) and serial sectioning – transmission electron microscopy (TEM). These results demonstrate the compatibility of the platform with optical microscopy, high-pressure freezing and electron microscopy. The platform can be extended to neuronal models of brain disease or development in future studies, enabling the investigation of subcellular processes at the nanoscale within two distinct groups of neurons in a functional neuronal pathway, as well as pharmacological testing and drug screening.
... It is widely established that APP mutations, altering Aβ production, can cause EOAD but the involvement of APP per se in its progression is not well understood 55 . However, synaptic function is affected at earliest stages of AD, partially independent from Aβ plaque formation and accompanied by disruption of excitatory/inhibitory balance in animal models as well as patients 6,7,48,56 . We were interested to see if and how APP manages to modulate excitatory and/or inhibitory neurotransmission in the absence of APP mutations or Aβ plaque formation. ...
Article
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The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer’s disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABAB receptors (GABABRs), subsequently decreasing the probability of neurotransmitter release. In this body of work, we were able to show that overexpression of wild-type human APP in mice (hAPPwt) causes early cognitive impairment, neuronal loss, and electrophysiological abnormalities in the absence of amyloid plaques and at very low levels of Aβ. hAPPwt mice exhibited neuronal overexcitation that was evident in EEG and increased long-term potentiation (LTP). Overexpression of hAPPwt did not alter GABAergic/glutamatergic receptor components or GABA production ability. Nonetheless, we detected a decrease of GABA but not glutamate that could be linked to soluble APP fragments, acting on presynaptic GABABRs and subsequently reducing GABA release. By using a specific presynaptic GABABR antagonist, we were able to rescue hyperexcitation in hAPPwt animals. Our results provide evidence that APP plays a crucial role in regulating inhibitory neurotransmission.
... Given the reports that in vivo models of AD display hyperactive cortical neurons (Busche and Konnerth, 2016), I wanted to test whether this excited cortical state would enhance the ability for tau internalisation. In an attempt to drive the system, I decided to test mild chronic stimulation with 4-AP (> 24 h) of primary cortical neurons in the presence of tau-GFP11 containing media. ...
Conference Paper
Tau pathology is well documented in Alzheimer's disease and its build up follows a stereotypical spread correlating with disease severity. This reveals an apparent anatomically linked spread of tau, supporting the hypothesis that tau can propagate via cell-to-cell transfer. However, a direct visualisation of tau entering the cytosol of a recipient cell and a full understanding of the mechanism at the basis of this process are still lacking. I have setup and optimised a strategy based on split-green fluorescent protein (GFP) to conclusively demonstrate cytosolic translocation of tau. Split-GFP is derived from the superfolder beta-barrel structure of GFPs truncated between 10th and 11th beta strands generating two non-fluorescent fragments named GFP1-10 and GFP11. In this project, the GFP11 is used to tag tau whereas the GFP1-10 is cytosolically expressed and acts as a sensor to detect the presence of tau in the cytoplasmic environment; only when the two GFP fragments associate will they reconstitute the fluorophore, thus maximising the signal to noise ratio. I have demonstrated the ability of the split-GFP assay to detect cellular uptake and release of tau into the cytosol in living cells. With this technique I have observed the real-time uptake dynamics of all six tau isoforms and the disease relevant P301S mutant and investigated potential mechanisms underpinning this process, including pH sensitivity and Rab GTPase activity. This assay has been tested both in cell-lines and primary neuronal cultures grown in custom-made microfluidic chambers, with the aim to improve the tools available to study tau propagation in vitro and in vivo.
... Alzheimer's disease leads to a hypersynchronous activity which was suggested to accelerate the progression of dementia [81]. Hypersynchronous activity, similar to ictal activity, was observed in both animal models of Alzheimer's disease and in clinical studies [82][83][84]. For instance, imaging studies using fMRI showed hyperactivity in the hippocampus, which was also accompanied by cognitive impairments affecting pattern separation [85]. ...
Article
Epileptogenesis is a complex and not well understood phenomenon. Here, we explore the hypothesis that epileptogenesis could be “hijacking” normal memory processes, and how this hypothesis may provide new directions for epilepsy treatment. First, we review similarities between the hypersynchronous circuits observed in epilepsy and memory consolidation processes involved in strengthening neuronal connections. Next, we describe the kindling model of seizures and its relation to long-term potentiation model of synaptic plasticity. We also examine how the strengthening of epileptic circuits is facilitated during the physiological slow wave sleep, similarly as episodic memories. Furthermore, we present studies showing that specific memories can directly trigger reflex seizures. The neuronal hypersynchrony in early stages of Alzheimer's disease, and the use of anti-epileptic drugs to improve the cognitive symptoms in this disease also suggests a connection between memory systems and epilepsy. Given the commonalities between memory processes and epilepsy, we propose that therapies for memory disorders might provide new avenues for treatment of epileptic patients.
... Animal models of Alzheimer's disease have shown increased neuronal firing in the vicinity of amyloid plaques. 4 Studies in humans have demonstrated that amyloid toxicity causes a loss of inhibitory terminals, 5 and amyloidosis (lower amyloid-β levels in cerebrospinal fluid) is associated with the existence of late-onset epilepsy of unknown aetiology in mild cognitive impairment (MCI) patients. 6 Finally, increased epileptiform activity (EA) has been found in brain regions typically affected by the neuropathology of Alzheimer's disease. ...
Article
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There is growing evidence for neuronal hyperexcitability in Alzheimer's disease. Hyperexcitability is associated with an increase in epileptiform activity and the disruption of inhibitory activity of interneurons. Interneurons fire at a high rate and are frequently associated with high-frequency oscillations in the gamma frequency band (30-150 Hz). It is unclear how hyperexcitability affects the organization of functional brain networks. A sample of 63 amnestic mild cognitive impairment patients underwent a magnetoencephalography resting-state recording with eyes closed. Twenty (31.75%) mild cognitive impairment patients had epileptiform activity. A cluster-based analysis of the magnetoencephalography functional connectivity revealed a region within the right temporal cortex whose global connectivity in the gamma frequency band was significantly reduced in patients with epileptiform activity relative to those without epileptiform activity. A subsequent seed-based analysis showed that this was largely due to weaker gamma band connectivity of this region with ipsilateral frontal and medial regions, and the upper precuneus area. In addition, this reduced functional connectivity was associated with higher grey matter atrophy across several cortical regions in the patients with epileptiform activity. These functional network disruptions and changes in brain physiology and morphology have important clinical implications as they may contribute to cognitive decline in mild cognitive impairment and Alzheimer's disease.
... Alterations of the glutamatergic/GABAergic balance, a homeostatic basis for appropriate information transfer in the brain, can occur in AD with early defect of the inhibitory circuits [186]. Mouse AD models also display an increased aberrant network activity which can be due to an imbalanced excitation/inhibition ratio [46,[187][188][189][190][191][192][193], and increased intrinsic excitability properties of CA1 hippocampal neurons [194]. In addition, the Aβo-induced increase in neuronal activity is paralleled with an impairment of hippocampal LTP, and both alterations can be normalized by boosting the GABA tone with anticonvulsant drugs such as levetiracetam or topiramate [195]. ...
Thesis
Le binge drinking (BD) est un mode de consommation d'alcool très répandu chez les jeunes adultes et qui se caractérise par une prise massive et épisodique d'alcool dans un laps de temps court afin d'atteindre rapidement l'état d’ivresse. Chez ces jeunes, le BD est responsable de perturbations des capacités cognitives et la consommation des femmes rattrape celle des hommes alors qu'elles seraient plus sensibles aux effets délétères de l'éthanol (EtOH) sur le cerveau. Dans ce contexte, il nous est apparu important de comprendre les différences liées au sexe dans les effets du BD sur le fonctionnement cérébral, et notamment la plasticité neuronale d’e l'hippocampe, mécanisme cellulaire de la mémoire et des apprentissages. Ainsi, les objectifs de ma thèse ont été i) d'explorer l'impact du cycle ovarien sur les effets du BD sur la plasticité neuronale de l'hippocampe, ii) de mesurer la modulation des effets de l'éthanol par les œstrogènes pendant l'adolescence chez la femelle et chez le mâle, et iii) de chercher les mécanismes d'action impliqués. Ainsi, nous avons enregistré chez la ratte adolescente la plasticité du réseau hippocampique ex vivo après une exposition courte à l'éthanol après 2 binges d'éthanol. Nous avons mis en évidence une abolition de la plasticité de type dépression à long terme (LTD) à 24h de délai, seulement lorsque l'administration d'éthanol était effectuée pendant le pic d'œstrogènes endogènes, suggérant une interaction entre éthanol et œstrogènes (E2). Pour vérifier cette hypothèse, nous avons mesuré chez des rattes pubères, prépubères, et chez des mâles adolescents les effets sur la DLT d'un traitement exogène d’E2+EtOH. L'abolition de la DLT a été observé à chaque fois. L'utilisation d'antagonistes spécifiques nous a permis de mettre en évidence l'implication des récepteurs aux œstrogènes, ainsi que de la sous-unité GluN2B des récepteurs NMDA dans ces résultats. Nous concluons que les œstrogènes pourrait être un facteur de vulnérabilité liés au genre vis-à-vis des effets de l'alcool sur les capacités cognitives chez les femelles, pendant l'adolescence
... NDD critically affect neuronal function, leading to the progressive loss of neurons in specific regions of the brain and the disruption of the neural network integrity (Yi et al., 2015;Busche and Konnerth, 2016;Choi et al., 2017;Osaki et al., 2018a;Fortanier et al., 2019;). An effective curative treatment for such disorders is still a challenge, since the molecular mechanisms causing cellular degeneration are still hypothetical (Cutsuridis and Perantonis, 2006;Calsolaro and Edison, 2016;J;Siney et al., 2018;Natarajan et al., 2019). ...
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The human brain is a complex organ composed of many different types of cells interconnected to create an organized system able to efficiently process information. Dysregulation of this delicately balanced system can lead to the development of neurological disorders, such as neurodegenerative diseases (NDD). To investigate the functionality of human brain physiology and pathophysiology, the scientific community has been generated various research models, from genetically modified animals to two- and three-dimensional cell culture for several decades. These models have, however, certain limitations that impede the precise study of pathophysiological features of neurodegeneration, thus hindering therapeutical research and drug development. Compartmentalized microfluidic devices provide in vitro minimalistic environments to accurately reproduce neural circuits allowing the characterization of the human central nervous system. Brain-on-chip (BoC) is allowing our capability to improve neurodegeneration models on the molecular and cellular mechanism aspects behind the progression of these troubles. This review aims to summarize and discuss the latest advancements of microfluidic models for the investigations of common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.
... In addition, Aβ is involved in complement activation in the drusen formation [5]. Aβ oligomers found in drusen are toxic to human retinal pigment epithelium and cultured SH-SY5Y human neuroblastoma cells [29], and these findings are consistent with studies in patients with early AD, where large amounts of these highly toxic oligomers are found in the brain, causing neuronal dysfunction and synaptic disruption [36]. This could explain the possible alterations found in both the retina and choroid of subjects at high genetic risk of developing AD, who are also part of this study, and which we have reported in a previous work [21,30]. ...
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Having a family history (FH+) of Alzheimer’s disease (AD) and being a carrier of at least one ɛ4 allele of the ApoE gene are two of the main risk factors for the development of AD. AD and age-related macular degeneration (AMD) share one of the main risk factors, such as age, and characteristics including the presence of deposits (Aβ plaques in AD and drusen in AMD); however, the role of apolipoprotein E isoforms in both pathologies is controversial. We analyzed and characterized retinal drusen by optical coherence tomography (OCT) in subjects, classifying them by their AD FH (FH- or FH+) and their allelic characterization of ApoE ɛ4 (ApoE ɛ4- or ApoE ɛ4+) and considering cardiovascular risk factors (hypercholesterolemia, hypertension, and diabetes mellitus). In addition, we analyzed the choroidal thickness by OCT and the area of the foveal avascular zone with OCTA. We did not find a relationship between a family history of AD or any of the ApoE isoforms and the presence or absence of drusen. Subjects with drusen show choroidal thinning compared to patients without drusen, and thinning could trigger changes in choroidal perfusion that may give rise to the deposits that generate drusen.
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A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ 1-42 -related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ 1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder with typical neuropathological hallmarks, such as neuritic plaques and neurofibrillary tangles, preferentially found at layers III and V. The distribution of both hallmarks provides the basis for the staging of AD, following a hierarchical pattern throughout the cerebral cortex. To unravel the background of this layer-specific vulnerability, we evaluated differential gene expression of supragranular and infragranular layers and subcortical white matter in both healthy controls and AD patients. We identified AD-associated layer-specific differences involving protein-coding and non-coding sequences, most of those present in the subcortical white matter, thus indicating a critical role for long axons and oligodendrocytes in AD pathomechanism. In addition, GO analysis identified networks containing synaptic vesicle transport, vesicle exocytosis and regulation of neurotransmitter levels. Numerous AD-associated layer-specifically expressed genes were previously reported to undergo layer-specific switches in recent hominid brain evolution between layers V and III, i.e., those layers that are most vulnerable to AD pathology. Against the background of our previous finding of accelerated evolution of AD-specific gene expression, here we suggest a critical role in AD pathomechanism for this phylogenetic layer-specific adaptation of gene expression, which is most prominently seen in the white matter compartment.
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In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered that neurotransmission to postsynaptic partners of R7 and their response are required to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structure. This model can be used to dissect cellular circuit mechanisms involved in the early events of axonal degeneration, allowing for a better understanding of how neurons cope with stress and lose their resilience capacities.
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Soluble amyloid precursor protein-alpha (sAPPα) is a multi-functional brain-derived protein that has neuroprotective, neurogenic and neurotropic properties. Moreover, it is known to facilitate synaptic function and promote neural repair. These properties suggest sAPPα may be useful as a therapeutic agent for the treatment of neurological diseases characterized by synaptic failure and neuronal loss, such as occurs in Alzheimer’s disease, and for neural repair following traumatic brain injury and stroke. However, sAPPα’s relatively large size and the difficulty of ongoing delivery of therapeutics to the brain mean this is not currently practicable. Importantly, however, sAPPα is composed of several neuroactive domains that each possess properties that collectively are remarkably similar to those of sAPPα itself. Here, we review the molecular structure of sAPPα and identify the domains that contribute to its overall functionality. Four peptide motifs present as possible targets for therapeutic development. We review their physiochemical and neuroactive properties, both within sAPPα and as isolated peptides, and discuss their potential for future development as multipurpose therapeutic agents for the treatment of Alzheimer’s disease and other disorders of neuronal function. Further, we discuss the role of heparin binding sites, found within sAPPα’s structure and overlapping with the neuroactive domains, as sites for interactions with effector proteins and synaptic receptors. The potential role of the neuroactive peptides known as Cationic Arginine-Rich Peptides (CARPs) as neuroprotective motifs is also reviewed. Mechanisms of peptide delivery to the brain are briefly discussed. Finally, we summarise the potential benefits and pitfalls of using the isolated peptides, either individually or in combination, for the treatment of neurological diseases.
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Cortical network hyperexcitability is an inextricable feature of Alzheimer’s disease (AD) that also might accelerate its progression. Seizures are reported in 10–22% of patients with AD, and subclinical epileptiform abnormalities have been identified in 21–42% of patients with AD without seizures. Accurate identification of hyperexcitability and appropriate intervention to slow the compromise of cognitive functions of AD might open up a new approach to treatment. Based on the results of several studies, epileptiform discharges, especially those with specific features (including high frequency, robust morphology, right temporal location, and occurrence during awake or rapid eye movement states), frequent small sharp spikes (SSSs), temporal intermittent rhythmic delta activities (TIRDAs), and paroxysmal slow wave events (PSWEs) recorded in long-term scalp electroencephalogram (EEG) provide sufficient sensitivity and specificity in detecting cortical network hyperexcitability and epileptogenicity of AD. In addition, magnetoencephalogram (MEG), foramen ovale (FO) electrodes, and computational approaches help to find subclinical seizures that are invisible on scalp EEGs. We performed a comprehensive analysis of the aforementioned electrophysiological biomarkers of AD-related seizures.
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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD is still puzzling, and new drugs development and clinical trials have high failure rates. Urgent outline of an integral (multi-target) and effective treatment of AD is needed. Accumulation of amyloid-β (Aβ) peptides is considered one of the fundamental neuropathological pillars of the disease, and its dyshomeostasis has shown a crucial role in AD onset. Therefore, many amyloid-targeted therapies have been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up and review studies focused on anti-amyloid strategies to summarize and analyze their current clinical potential. Combination of anti-Aβ therapies with new developing early detection biomarkers and other therapeutic agents acting on early functional AD changes will be highlighted in this review. Near-term approval seems likely for several drugs acting against Aβ, with recent FDA approval of a monoclonal anti-Aβ oligomers antibody -aducanumab- raising hopes and controversies. We conclude that, development of oligomer-epitope specific Aβ treatment and implementation of multiple improved biomarkers and risk prediction methods allowing early detection, together with therapies acting on other factors such as hyperexcitability in early AD, could be the key to slowing this global pandemic.
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A strategy to gain insight into early changes that may predispose people to Alzheimer's disease (AD) is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ∼20–30 years have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN), which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18–25 years underwent resting-state proton magnetic resonance spectroscopy (¹H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, or in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Our findings suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or possibly may precede, alterations in local resting-state PMC neurotransmitters, thus informing our understanding of the spatio-temporal sequence of early network alterations underlying APOE E4 related AD risk.
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Disruptions to the central excitatory-inhibitory (E/I) balance are thought to be related to aging and underlie a host of neural pathologies, including Alzheimer's disease. Aging may induce an increase in excitatory signaling, causing an E/I imbalance, which has been linked to shorter lifespans in mice, flies, and worms. In humans, extended longevity correlates to greater repression of genes involved in excitatory neurotransmission. The repressor element-1 silencing transcription factor (REST) is a master regulator in neural cells and is believed to be upregulated with senescent stimuli, whereupon it counters hyperexcitability, insulin/insulin-like signaling pathway activity, oxidative stress, and neurodegeneration. This review examines the putative mechanisms that distort the E/I balance with aging and neurodegeneration, and the putative roles of REST in maintaining neuronal homeostasis.
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Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting the aging population. Despite many studies, there remains an urgent need to identify the root causes of AD, together with potential treatments. Cerebral organoid technology has made it possible to model human neurophysiology and disease with increasing accuracy in patient-derived tissue cultures. Here, we review the most recent advances in modeling AD in organoids and other engineered three-dimensional cell culture systems. Early studies demonstrated that familial AD patient-derived organoids robustly develop disease pathology. Ongoing work has expanded this focus to investigate the genetic and environmental causes of late-onset sporadic AD and harness organoids for high-throughput drug screens. Future organoid models will need to incorporate additional cell types and tissues implicated in disease pathogenesis, including microglia and vasculature. We anticipate the continuation of this rapid progress in developing cerebral organoid technology toward facilitating our understanding of and informing treatment strategies for AD.
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Protein kinases represent important signaling hubs for a variety of biological functions. Many kinases are traditionally studied for their roles in cancer cell biology, but recent advances in neuroscience research show repurposed kinase function to be important for nervous system development and function. Two members of the AMP-activated protein kinase (AMPK) related family, Nuak1 and Nuak2, have drawn attention in neuroscience due to their mutations in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, and intellectual disability (ID). Furthermore, Nuak kinases have also been implicated in tauopathy and other disorders of aging. This review highlights what is known about the Nuak kinases in nervous system development and disease and explores the possibility of Nuak kinases as targets for therapeutic innovation.
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Microglia can interact with glutamatergic neurons and, through control of synaptic elements, regulate their physiological function. Much less is known about the partnership between microglia and GABAergic inhibitory interneurons. Here, we compared the interactions between microglia and parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the CA1 hippocampal area of APP/PS1 transgenic mice that mimic certain aspects of the Alzheimer's disease (AD). We first uncovered a high level of interactions between microglia and two types of interneurons, with 98% of SOM+ and 90% of PV+ cells receiving different types of putative microglial contacts. The latter included the microglia soma to the interneuron soma (SomaMG-to-SomaIN), the microglia process to the interneuron soma (ProcessMG-to-SomaIN) and the microglia process to the interneuron dendrite (ProcessMG-to-DendIN) interactions. Moreover, we found significantly larger areas of interaction for the SomaMG-to-SomaIN and the ProcessMG-to-DendIN type of contacts between microglia and SOM+ cells. In contrast, PV+ cells exhibited larger areas for the ProcessMG-to-SomaIN interactions. Second, in APP/PS1 mice, whereas the overall microglia interactions with interneurons remained preserved, the fraction of interneurons receiving putative microglia contacts on their dendrites was reduced, and larger areas of interactions were observed for somatic contacts, suggesting a stronger modulation of the interneuron output by microglia in AD. In summary, these results reveal microglia as important partners of hippocampal PV+ and SOM+ GABAergic cells, with interneuron type-specific pattern of interactions. Thus, microglia may play an essential role in the operation of interneurons under normal conditions and their dysfunction in disease. This article is protected by copyright. All rights reserved
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Since the first demonstrations of network hyperexcitability in scientific models of Alzheimer's disease (AD) a growing body of clinical studies have identified subclinical epileptiform activity and associated cognitive decline in patients with AD. An obvious problem presented in these studies is lack of sensitive measures to detect and quantify network hyperexcitability in human subjects. In this study we examined whether altered neuronal synchrony can be a surrogate marker to quantify network hyperexcitability in patients with AD. Using magnetoencephalography (MEG) at rest, we studied thirty AD patients without subclinical epileptiform activity (AD-EPI-), and twenty AD patients with subclinical epileptiform activity (AD-EPI+), and thirty-five age-matched controls. Presence of subclinical epileptiform activity was assessed in patients with AD by long-term video-electroencephalography (LTM-EEG) and a 1-hour resting magnetoencephalography with simultaneous EEG (M/EEG). Using the resting-state source-space reconstructed MEG signal, in patients and controls we computed the global imaginary coherence in alpha (8-12 Hz) and delta-theta (2-8 Hz) oscillatory frequencies. We found that AD-EPI+ patients have greater reductions in alpha imaginary coherence and greater enhancements in delta-theta imaginary coherence, than AD-EPI- patients and that these changes can distinguish between AD-EPI+ and AD-EPI- patients with high accuracy. Finally, a principal component regression analysis showed that the variance of frequency-specific neuronal synchrony predicts longitudinal changes in Mini Mental State Exam (MMSE), in patients and controls. Our results demonstrate that quantitative neurophysiological measures are sensitive biomarkers of network hyperexcitability and can be used to improve diagnosis and to select appropriate patients for the right therapy in the next generation clinical trials. The current results provide an integrative framework for investigating network hyperexcitability and network dysfunction, together with their cognitive and clinical correlates in patients with AD.
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Background: Effective treatment of Alzheimer's disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. Objective: To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. Methods: We quantified intracellular and extracellular antibody labelling of Aβ 42 in 6 regions of the central auditory system from p14 to p150. Results: Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aβ 42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. Conclusion: These results suggest that Aβ 42 accumulation, but not plaques, may impair gap detection.
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Background Although growing evidence links beta-amyloid (Aβ) and neuronal hyperexcitability in preclinical mouse models of Alzheimer’s disease (AD), a similar association in humans is yet to be established. The first aim of the study was to determine the association between elevated Aβ (Aβ+) and cognitive processes measured by the P3 event-related potential (ERP) in cognitively normal (CN) older adults. The second aim was to compare the event-related power between CNAβ+ and CNAβ−. Methods Seventeen CNAβ+ participants (age: 73 ± 5, 11 females, Montreal Cognitive Assessment [MoCA] score 26 ± 2) and 17 CNAβ- participants group-matched for age, sex, and MOCA completed a working memory task ( n -back with n = 0, 1, 2) test while wearing a 256-channel electro-encephalography net. P3 peak amplitude and latency of the target, nontarget and task difference effect (nontarget−target), and event-related power in the delta, theta, alpha, and beta bands, extracted from Fz, Cz, and Pz, were compared between groups using linear mixed models. P3 amplitude of the task difference effect at Fz and event-related power in the delta band were considered main outcomes. Correlations of mean Aβ standard uptake value ratios (SUVR) using positron emission tomography with P3 amplitude and latency of the task difference effect were analyzed using Pearson Correlation Coefficient r . Results The P3 peak amplitude of the task difference effect at Fz was lower in the CNAβ+ group ( P = 0.048). Similarly, power was lower in the delta band for nontargets at Fz in the CNAβ+ participants ( P = 0.04). The CNAβ+ participants also demonstrated higher theta and alpha power in channels at Cz and Pz, but no changes in P3 ERP. Strong correlations were found between the mean Aβ SUVR and the latency of the 1-back ( r = − 0.69; P = 0.003) and 2-back ( r = − 0.69; P = 0.004) of the task difference effect at channel Fz in the CNAβ+ group. Conclusions Our data suggest that the elevated amyloid in cognitively normal older adults is associated with neuronal hyperexcitability. The decreased P3 task difference likely reflects early impairments in working memory processes. Further research is warranted to determine the validity of ERP in predicting clinical, neurobiological, and functional manifestations of AD.
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Background: Recent studies demonstrated that brain hypersynchrony is an early sign of dysfunction in Alzheimer's disease (AD) that can represent a proxy for clinical progression. Conversely, non-pharmacological interventions, such as cognitive training (COGTR), are associated with cognitive gains that may be underpinned by a neuroprotective effect on brain synchrony. Objective: To study the potential of COGTR to modulate brain synchrony and to eventually revert the hypersynchrony phenomenon that characterizes preclinical AD. Methods: The effect of COGTR was examined in a sample of healthy controls (HC, n = 41, 22 trained) and individuals with subjective cognitive decline (SCD, n = 49, 24 trained). Magnetoencephalographic (MEG) activity and neuropsychological scores were acquired before and after a ten-week COGTR intervention aimed at improving cognitive function and daily living performance. Functional connectivity (FC) was analyzed using the phase-locking value. A mixed-effects ANOVA model with factors time (pre-intervention/post-intervention), training (trained/non-trained), and diagnosis (HC/SCD) was used to investigate significant changes in FC. Results: We found an average increase in alpha-band FC over time, but the effect was different in each group (trained and non-trained). In the trained group (HC and SCD), we report a reduction in the increase in FC within temporo-parietal and temporo-occipital connections. In the trained SCD group, this reduction was stronger and showed a tentative correlation with improved performance in different cognitive tests. Conclusion: COGTR interventions could mitigate aberrant increases in FC in preclinical AD, promoting brain synchrony normalization in groups at a higher risk of developing dementia.
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Neural activity coordinated across different scales from neuronal circuits to large-scale brain networks gives rise to complex cognitive functions. Bridging the gap between micro- and macro-scale processes, we present a novel framework based on the maximum entropy model to infer a hybrid resting state structural connectome, representing functional interactions constrained by structural connectivity. We demonstrate that the structurally informed network outperforms the unconstrained model in simulating brain dynamics; wherein by constraining the inference model with the network structure we may improve the estimation of pairwise BOLD signal interactions. Further, we simulate brain network dynamics using Monte Carlo simulations with the new hybrid connectome to probe connectome-level differences in excitation-inhibition balance between apolipoprotein E (APOE)-ε4 carriers and noncarriers. Our results reveal sex differences among APOE-ε4 carriers in functional dynamics at criticality; specifically, female carriers appear to exhibit a lower tolerance to network disruptions resulting from increased excitatory interactions. In sum, the new multimodal network explored here enables analysis of brain dynamics through the integration of structure and function, providing insight into the complex interactions underlying neural activity such as the balance of excitation and inhibition.
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The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer's disease as well as other neurodegenerative diseases.
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Alzheimer's disease (AD) manifests with memory loss and spatial disorientation. AD pathology starts in the entorhinal cortex, making it likely that local neural correlates of spatial navigation, particularly grid cells, are impaired. Grid-cell-like representations in humans can be measured using functional magnetic resonance imaging. We found that young adults at genetic risk for AD (APOE-ε4 carriers) exhibit reduced grid-cell-like representations and altered navigational behavior in a virtual arena. Both changes were associated with impaired spatial memory performance. Reduced grid-cell-like representations were also related to increased hippocampal activity, potentially reflecting compensatory mechanisms that prevent overt spatial memory impairment in APOE-e 4 carriers. Our results provide evidence of behaviorally relevant entorhinal dysfunction in humans at genetic risk for AD, decades before potential disease onset. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved.
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Synaptic dysfunction is a hallmark of many neurodegenerative and psychiatric brain disorders, yet we know little about the mechanisms that underlie synaptic vulnerability. Although neuroinflammation and reactive gliosis are prominent in virtually every CNS disease, glia are largely viewed as passive responders to neuronal damage rather than drivers of synaptic dysfunction. This perspective is changing with the growing realization that glia actively signal with neurons and influence synaptic development, transmission and plasticity through an array of secreted and contact-dependent signals. We propose that disruptions in neuron-glia signaling contribute to synaptic and cognitive impairment in disease. Illuminating the mechanisms by which glia influence synapse function may lead to the development of new therapies and biomarkers for synaptic dysfunction.
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Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.
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Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
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