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Impairments of neural circuit function in Alzheimer's disease

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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’.
Cite this article: Busche MA, Konnerth A.
2016 Impairments of neural circuit function
in Alzheimer’s disease. Phil. Trans. R. Soc. B
371: 20150429.
Accepted: 31 March 2016
One contribution of 15 to a Theo Murphy
meeting issue ‘Evolution brings Ca
ATP together to control life and death’.
Subject Areas:
Alzheimer’s disease, amyloid-b,in vivo
calcium imaging, mouse models
Authors for correspondence:
Marc Aurel Busche
Arthur Konnerth
Impairments of neural circuit function
in Alzheimer’s disease
Marc Aurel Busche1,2,3,4 and Arthur Konnerth1,3,4
Institute of Neuroscience, and
Department of Psychiatry and Psychotherapy, Technical University of Munich,
Munich, Germany
Munich Cluster for Systems Neurology (SyNergy), and
Center of Integrated Protein Science Munich (CIPSM),
Munich, Germany
An essential feature of Alzheimer’s disease (AD) is the accumulation of amy-
loid-b(Ab) 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 Aboligomers and amyloid plaques alter the
function of local neuronal circuits and large-scale networks by disrupting
the balance of synaptic excitation and inhibition (E/Ibalance) in the brain.
The analysis of mouse models of AD revealed that an Ab-induced change
of the E/Ibalance 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 dys-
functions in the pathophysiological cascade initiated by abnormal Ab
accumulation. Therapeutics that correct the E/Ibalance in early AD may pre-
vent 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
and ATP
together to control life and death’.
1. Introduction
Alzheimer’s disease (AD) is the most common cause of intellectual decline in
the elderly population worldwide [1]. AD is characterized by slowly progres-
sive memory deficits, cognitive impairments and dementia. The diagnosis is
established by these clinical features combined with biomarker evidence for
amyloid-b(Ab) accumulation (as measured by cerebrospinal fluid (CSF) levels
of Ab
or positron emission tomography (PET)-amyloid imaging) and/or neur-
onal degeneration (as measured by CSF levels of tau and phosphorylated tau as
well as fluorodeoxyglucose (FDG)-PET or structural magnetic resonance imaging
(MRI)) in the brain [2]. Current treatments are unsatisfactory as they provide only
symptomatic relief and are effective in only a subset of affected individuals [3].
It is becoming increasingly clear that the pathogenic cascade that causes AD
begins decades before first clinical symptoms become evident [4,5]. For instance,
in people at risk of AD abnormal Abaccumulation and amyloid deposition, as
measured by CSF
and amyloid-PET, was detected 25 years before symptom
onset [6]. There is growing evidence from functional MRI (fMRI) that this ‘precli-
nical’ stage of AD is associated with profound functional alterations of brain
networks that seem to be structurally largely intact. For example, hippocampal
hyperactivation and impaired deactivation of the default-mode network during
memory-encoding have been demonstrated in people at genetic risk for AD
[79], cognitively normal individuals with evidence for Abaccumulation
[10– 12] and people with early AD [1315].
Major unresolved issues include the questions of why neuronal circuits
become dysfunctional in response to high Ablevels and how circuit abnormal-
ities can be repaired. As these problems cannot be studied easily in humans
with existing techniques, transgenic mouse models overproducing human
mutant Abare in many cases the method of choice for such investigations.
Indeed, recent experimental evidence obtained in mouse model studies suggest
&2016 The Author(s) Published by the Royal Society. All rights reserved.
... Frontiers in Human Neuroscience 09 Alzheimer's disease (Koch et al., 2022) and may contribute to cognitive impairment (Busche and Konnerth, 1700;Palop and Mucke, 2016). However, while a major emphasis in prior research has focused on dysfunction of the glutamatergic system, accumulating evidence links inhibitory GABAergic interneurons to excitatory/inhibitory imbalance as a potential early contributor to cognitive impairment in both aging (Oh et al., 2010;Gallagher et al., 2019) and disease Govindpani et al., 2017). ...
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Introduction: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that uses pulsed magnetic fields to affect the physiology of the brain and central nervous system. Repetitive TMS (rTMS) has been used to study and treat several neurological conditions, but its complex molecular basis is largely unexplored. Methods: Utilizing three experimental rat models (in vitro, ex vivo, and in vivo) and employing genome-wide microarray analysis, our study reveals the extensive impact of rTMS treatment on gene expression patterns. Results: These effects are observed across various stimulation protocols, in diverse tissues, and are influenced by time and age. Notably, rTMS-induced alterations in gene expression span a wide range of biological pathways, such as glutamatergic, GABAergic, and anti-inflammatory pathways, ion channels, myelination, mitochondrial energetics, multiple neuron-and synapse-specific genes. Discussion: This comprehensive transcriptional analysis induced by rTMS stimulation serves as a foundational characterization for subsequent experimental investigations and the exploration of potential clinical applications.
... Similarly, older adults in early stages of AD-related cognitive impairment exhibit generalized patterns of brain activity during associative memory task performance (Oedekoven, Jansen, Keidel, Kircher, & Leube, 2015) and rest (Bai et al., 2008), as well as memory-related hyperactivation of hippocampal and default mode regions (Dickerson et al., 2005;Nyberg, Andersson, Lundquist, Salami, & Wahlin, 2019). Resting and memory task-related hyperactivation of these regions also appears in young and older adults with increased genetic risk (i.e., family history or APOE4 allele) of AD (Bookheimer et al., 2000;Filippini et al., 2009;Machulda et al., 2011;Quiroz et al., 2010) and may represent an early sign of pathological Aβ accumulation (Busche & Konnerth, 2016;R. A. Sperling et al., 2009). ...
p>Late-onset Alzheimer's disease (AD) disproportionately affects women compared to men. Episodic memory decline is one of the earliest and most pronounced deficits observed in AD. However, it remains unclear whether sex influences episodic memory-related brain function in cognitively intact older adults at risk of developing AD. Here we used task-based multivariate partial least squares analysis to examine sex differences in episodic memory-related brain activity and brain activity-behavior correlations in a matched sample of cognitively intact older women and men with a family history of AD from the PREVENT-AD cohort study in Montreal, Canada (Mage=63.03±3.78; Meducation=15.41±3.40). We observed sex differences in task-related brain activity and brain activity-behavior correlations during the encoding of object-location associative memories and object-only item memory, and the retrieval of object only item memories. Our findings suggest a generalization of episodic memory-related brain activation and performance in women compared to men. Follow up analyses should test for sex differences in the relationship between brain activity patterns and performance longitudinally, in association with risk factors for AD development. </p
... The overall spectral shift towards decreased power in the low-frequency delta band and increased power in the high-frequency beta bands in the preclinical AD group are consistent with neural hyperexcitability, a finding increasingly reported in the literature (Devos et al., 2022;Targa Dias Anastacio et al., 2022). Although the drivers of this increased neural excitability in this preclinical phase of AD are still unclear (Targa Dias Anastacio et al., 2022), studies in animal models of AD have found a strong link between hyperexcitability and Aβ accumulation near the hyperexcitable neurons (Busche & Konnerth, 2016). Previous EEG studies also reported that individuals with MCI have higher power from theta to beta bands than controls during working memory tasks (Jiang, 2005). ...
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There is increasing evidence of the usefulness of electroencephalography (EEG) as an early neurophysiological marker of preclinical AD. Our objective was to apply machine learning approaches on event-related oscillations to discriminate preclinical AD from neurotypical controls. Twenty-two preclinical AD participants who were cognitively normal with elevated amyloid and 21 cognitively normal with no elevated amyloid controls completed n-back working memory tasks (n= 0, 1, 2). EEG signals were recorded through a high-density sensor net. The event-related spectral changes were extracted using the discrete wavelet transform in the delta, theta, alpha, and beta bands. The support vector machine (SVM) machine learning method was employed to classify participants, and classification performance was assessed using the Area Under the Curve (AUC) metric. The relative power of the beta and delta bands outperformed other frequency bands with higher AUC values. The 2-back task obtained higher AUC values than the 0 and 1-back tasks. The highest AUC values were from the 2-back task beta band (AUC = 0.86) and delta bands (AUC = 0.85) nontarget data. This study demonstrates the promise of using machine learning on EEG event-related oscillations from working memory tasks to detect preclinical AD.
... Impaired homeostatic regulation may lead to synaptic and neural network instability, a common feature linked to various neurologic disorders (Wondolowski and Dickman, 2013;Bourgeron, 2015;Styr and Slutsky, 2018). While a compromised homeostatic regulation could potentially induce unbalanced excitation and inhibition, leading to neurodegeneration in AD, the underlying molecular and cellular mechanisms associating homeostatic plasticity with disease pathology remain largely undefined (Busche and Konnerth, 2016). ...
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Destabilization of neural activity caused by failures of homeostatic regulation has been hypothesized to drive the progression of Alzheimer’s Disease (AD). However, the underpinning mechanisms that connect synaptic homeostasis and the disease etiology are yet to be fully understood. Here, we demonstrated that neuronal overexpression of Amyloid β (Aβ) causes abnormal histone acetylation in peripheral glia and completely diminishes Presynaptic Homeostatic Potentiation (PHP) at the neuromuscular junction in Drosophila . The synaptic deficits caused by Aβ overexpression in motoneurons are associated with motor function impairment at the adult stage. Moreover, we found that a Sphingosine analogue drug, Fingolimod, ameliorates synaptic homeostatic plasticity impairment, abnormal glial histone acetylation, and motor behavior defects in the Aβ models. We further demonstrated that perineurial glial Sphingosine kinase 2 ( Sk2 ) is not only required for PHP, but also plays a beneficial role in modulating PHP in the Aβ models. Glial overexpression of Sk2 rescues PHP, glial histone acetylation, and motor function deficits that are associated with Aβ in Drosophila . Finally, we showed that glial overexpression of Sk2 restores PHP and glial histone acetylation in a genetic loss-of-function mutant of the Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex, strongly suggesting that Sk2 modulates PHP through epigenetic regulation. Both male and female animals were used in the experiments and analyses in this study. Collectively, we provided genetic evidence demonstrating that abnormal glial epigenetic alterations in Aβ models in Drosophila are associated with the impairment of PHP and that the Sphingosine signaling pathway displays protective activities in stabilizing synaptic physiology. Significance Statement Fingolimod, an oral drug to treat Multiple Sclerosis, is phosphorylated by Sphingosine kinases to generate its active form. It is known that Fingolimod enhances the cognitive function in mouse models of Alzheimer's Disease (AD), but the role of Sphingosine kinases in AD is not clear. We bridge this knowledge gap by demonstrating the relationship between impaired homeostatic plasticity and AD. We show that Sphingosine kinase 2 ( Sk2 ) in glial cells is necessary for homeostatic plasticity and glial Sk2 -mediated epigenetic signaling has a protective role in synapse stabilization. Our findings demonstrate the potential of the glial Sphingosine signaling as a key player in glia-neuron interactions during homeostatic plasticity, suggesting it could be a promising target for sustaining synaptic function in AD.
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The pathophysiological process of Alzheimer's disease (AD) is believed to begin many years before the formal diagnosis of AD dementia. This protracted preclinical phase offers a crucial window for potential therapeutic interventions, yet its comprehensive characterization remains elusive. Accumulating evidence suggests that amyloid-β (Aβ) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD. At the same time, neural activity can also facilitate Aβ accumulation through intricate feed-forward interactions, complicating elucidating the conditions governing Aβ-dependent hyperactivity and its diagnostic utility. In this study, we use biophysical modeling to shed light on such conditions. Our analysis reveals that the inherently nonlinear nature of the underlying molecular interactions can give rise to various modes of hyperactivity emergence. This diversity in the mechanisms of hyperactivity may ultimately account for a spectrum of AD manifestations.
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GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input–output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer’s disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, prior to the onset of memory impairments, we found early hyperexcitability in MECII stellate and pyramidal cells’ intrinsic properties, but this was balanced by a relative reduction in synaptic excitation compared to inhibition (E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this post-symptomatic time point, which may contribute to the emergence of memory deficits in AD. Significance Statement Alzheimer’s disease (AD) causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the medial entorhinal cortex (MEC) have altered excitability. Before the onset of memory impairments, neurons in layer 2 of MEC had increased intrinsic excitability, but this was balanced by reduced inputs onto the cell. However, after the onset of memory impairments, stellate cells in MEC became further hyperexcitable, with increased excitability exacerbated by increased synaptic inputs. Thus, it appears that MEC stellate cells are uniquely disrupted during the progression of memory deficits and may contribute to cognitive deficits in AD.
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Functional disruption of the medial temporal lobe-dependent networks is thought to underlie episodic memory deficits in aging and Alzheimer’s disease. Previous studies revealed that the anterior medial temporal lobe is more vulnerable to pathological and neurodegenerative processes in Alzheimer’s disease. In contrast, cognitive and structural imaging literature indicates posterior, as opposed to anterior, medial temporal lobe vulnerability in normal aging. However, the extent to which Alzheimer’s and aging-related pathological processes relate to functional disruption of the medial temporal lobe-dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity alterations in the medial temporal lobe and its immediate functional neighborhood – the Anterior-Temporal and Posterior-Medial brain networks – in normal agers, individuals with preclinical Alzheimer’s disease, and patients with Mild Cognitive Impairment or mild dementia due to Alzheimer’s disease. In the Anterior-Temporal network and in the perirhinal cortex, in particular, we observed an inverted ‘U-shaped’ relationship between functional connectivity and Alzheimer’s stage. According to our results, the preclinical phase of Alzheimer’s disease is characterized by increased functional connectivity between the perirhinal cortex and other regions of the medial temporal lobe, as well as between the anterior medial temporal lobe and its one-hop neighbors in the Anterior-Temporal system. This effect is no longer present in symptomatic Alzheimer’s disease. Instead, patients with symptomatic Alzheimer’s disease displayed reduced hippocampal connectivity within the medial temporal lobe as well as hypoconnectivity within the Posterior-Medial system. For normal aging, our results led to three main conclusions: (1) intra-network connectivity of both the Anterior-Temporal and Posterior-Medial networks declines with age; (2) the anterior and posterior segments of the medial temporal lobe become increasingly decoupled from each other with advancing age; and, (3) the posterior subregions of the medial temporal lobe, especially the parahippocampal cortex, are more vulnerable to age-associated loss of function than their anterior counterparts. Together, the current results highlight evolving medial temporal lobe dysfunction in Alzheimer’s disease and indicate different neurobiological mechanisms of the medial temporal lobe network disruption in aging vs. Alzheimer’s disease.
Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multilayer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in the mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples, altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implies that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.
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Unlabelled: Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate β-amyloid (Aβ) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown. Using viral-mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs), we show in two AD-like mouse models that chronic intermittent increases or reductions of activity have opposite effects on Aβ deposition. Neural activity reduction markedly decreases Aβ aggregation in regions containing axons or dendrites of DREADD-expressing neurons, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Importantly, activity attenuation is associated with a reduction in axonal dystrophy and synaptic loss around amyloid plaques. Thus, modulation of neural activity could constitute a potential therapeutic strategy for ameliorating amyloid-induced pathology in AD. Significance statement: A novel chemogenetic approach to upregulate and downregulate neuronal activity in Alzheimer's disease (AD) mice was implemented. This led to the first demonstration that chronic intermittent attenuation of neuronal activity in vivo significantly reduces amyloid deposition. The study also demonstrates that modulation of β-amyloid (Aβ) release can occur at both axonal and dendritic fields, suggesting the involvement of synaptic and nonsynaptic Aβ release mechanisms. Activity reductions also led to attenuation of the synaptic pathology associated with amyloid plaques. Therefore, chronic attenuation of neuronal activity could constitute a novel therapeutic approach for AD.
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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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Early signs of dementia There is currently no cure for Alzheimer's disease. One of the reasons could be that interventions start too late, when there is already irreversible damage to the brain. Developing a biomarker that would help to effectively start therapy at very early stages of the disease is thus of high interest. Kunz et al. studied neural correlates of spatial navigation in the entorhinal cortex in control study participants and individuals at risk of developing Alzheimer's. The at-risk group showed a different brain signal many decades before the onset of the disease, and they navigated differently in a virtual environment. Science , this issue p. 430
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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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Importance 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. Objective 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). Data Sources 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. Study Selection Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Data Extraction and Synthesis 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. Main Outcomes and Measures 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. Results 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. Conclusions and Relevance 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.
The amyloid hypothesis for Alzheimer's disease (AD) posits a neuron-centric, linear cascade initiated by Aβ and leading to dementia. This direct causality is incompatible with clinical observations. We review evidence supporting a long, complex cellular phase consisting of feedback and feedforward responses of astrocytes, microglia, and vasculature. The field must incorporate this holistic view and take advantage of advances in single-cell approaches to resolve the critical junctures at which perturbations initially amenable to compensatory feedback transform into irreversible, progressive neurodegeneration.
Among the most promising approaches for treating Alzheimer´s disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies. © 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
Alzheimer's disease is a chronic illness with long preclinical and prodromal phases (20 years) and an average clinical duration of 8–10 years. The disease has an estimated prevalence of 10–30% in the population >65 years of age with an incidence of 1–3%. Most patients with Alzheimer's disease (>95%) have the sporadic form, which is characterized by a late onset (80–90 years of age), and is the consequence of the failure to clear the amyloid-β (Aβ) peptide from the interstices of the brain. A large number of genetic risk factors for sporadic disease have been identified. A small proportion of patients (<1%) have inherited mutations in genes that affect processing of Aβ and develop the disease at a much younger age (mean age of ∼45 years). Detection of the accumulation of Aβ is now possible in preclinical and prodromal phases using cerebrospinal fluid biomarkers and PET. Several approved drugs ameliorate some of the symptoms of Alzheimer's disease, but no current interventions can modify the underlying disease mechanisms. Management is focused on the support of the social networks surrounding the patient and the treatment of any co-morbid illnesses, such as cerebrovascular disease.
Alzheimer's disease (AD) is associated with defects of synaptic connectivity. Such defects may not be restricted to local neuronal interactions but may extend to long-range brain activities, such as slow-wave oscillations that are particularly prominent during non-rapid eye movement (non-REM) sleep and are important for integration of information across distant brain regions involved in memory consolidation. There is increasing evidence that sleep is often impaired in AD, but it is unclear whether this impairment is directly related to amyloid-β (Aβ) pathology. Here we demonstrate that slow-wave activity is severely altered in the neocortex, thalamus and hippocampus in mouse models of AD amyloidosis. Most notably, our results reveal an Aβ-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity. The finding that the impairment can be rescued by enhancing GABAAergic inhibition identifies a synaptic mechanism underlying Aβ-dependent large-scale circuit dysfunction.