Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology

Roh, Jee Hoon; Huang, Yafei; Bero, Adam W.; Kasten, Tom; Stewart, Floy R.; Bateman, Randall J.; Holtzman, David M.

doi:10.1126/scitranslmed.3004291

Cited by 503 publications

(491 citation statements)

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“…The sleep-wake changes described in APP-PS1 mice may be due to induced changes in synaptic activity and excitability occurring in brain regions affected by amyloid deposition. 37 In humans, a recent study found that individuals diagnosed with AD had fewer neurons than controls in the intermediate nucleus, a brain region that is thought to promote sleep by inhibiting wake-promoting brain regions. 38 Additionally, the impairment in sleep-dependent declarative memory consolidation observed in subjects with high amyloid load was found to be mediated by the loss in frontal SWA, 39 suggesting that changes in SWS lie downstream of Aβ42 deposition.…”

Section: Discussionmentioning

confidence: 99%

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly

Varga

Wohlleber

Giménez

et al. 2016

Sleep

159

130

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Study Objectives: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (Aβ). We thus aimed to examine relationships between concentrations of Aβ42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. Methods: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF Aβ42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" Aβ42 groups to compare SWS bout length using survival analyses. Results: A significant inverse correlation was found between CSF Aβ42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF Aβ42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF Aβ42. Conclusions: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF Aβ42, suggesting that disturbed sleep might drive an increase in soluble brain Aβ levels prior to amyloid deposition.

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Section: Discussionmentioning

confidence: 99%

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly

Varga

Wohlleber

Giménez

et al. 2016

Sleep

159

130

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“…Polysomnographic sleep-wake cycle analysis of mice was performed as described previously (Bero et al 2011;Roh et al 2012). Briefly, EEG and electromyogram (EMG) electrodes were implanted simultaneously 10 d prior to recording.…”

Section: Sleep Physiologymentioning

confidence: 99%

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation

et al. 2013

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Hypocretin (orexin; Hcrt)-containing neurons of the hypothalamus are essential for the normal regulation of sleep and wake behaviors and have been implicated in feeding, anxiety, depression, and reward. The absence of these neurons causes narcolepsy in humans and model organisms. However, little is known about the molecular phenotype of these cells; previous attempts at comprehensive profiling had only limited sensitivity or were inaccurate. We generated a Hcrt translating ribosome affinity purification (bacTRAP) line for comprehensive translational profiling of all ribosome-bound transcripts in these neurons in vivo. From this profile, we identified >6000 transcripts detectably expressed above background and 188 transcripts that are highly enriched in these neurons, including all known markers of the cells. Blinded analysis of in situ hybridization databases suggests that 60% of these are expressed in a Hcrt marker-like pattern. Fifteen of these were confirmed with double labeling and microscopy, including the transcription factor Lhx9. Ablation of this gene results in a >30% loss specifically of Hcrt neurons, without a general disruption of hypothalamic development. Polysomnography and activity monitoring revealed a profound hypersomnolence in these mice. These data provide an in-depth and accurate profile of Hcrt neuron gene expression and suggest that Lhx9 may be important for specification or survival of a subset of these cells.[Keywords: translational profiling; hypocretin; orexin; bacTRAP; Lhx9; narcolepsy] Supplemental material is available for this article. Narcolepsy is a profound disorder of sleep regulation, characterized by excessive daytime sleepiness, sleep attacks, cataplexy, and sleep-onset REM (rapid eye movement) periods. Studies indicate that narcolepsy, especially when accompanied by cataplexy, is due to the absence of hypocretinergic neurons and signaling (Nishino et al. 2000;Thannickal et al. 2000;Bourgin et al. 2008). The hypocretins (Hcrts; also called orexins) are peptidergic neurotransmitters used by a discrete population of neurons in the lateral hypothalamus Sakurai et al. 1998). In model organisms, disruption of the gene encoding the Hcrt peptides or a Hcrt receptor (Chemelli et al. 1999;Lin et al. 1999) or, alternatively, the ablation of the neurons producing Hcrt (Gerashchenko et al. 2001;Hara et al. 2001;Zhang et al. 2007) recapitulates features of narcolepsy. In humans, there are two variations of the disorder: narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwoC). NC is strongly linked and associated with the HLA DQB1*0602 allele, a T-cell receptor locus, and P2RY11, a receptor that can regulate immune cell survival (Hallmayer et al. 2009;Kornum et al. 2011). This strongly suggests involvement of the immune system in the etiology of NC, while the involvement in NwoC is less clear. Cold Spring Harbor Laboratory Press on May 13, 2018 -Published by genesdev.cshlp.org Downloaded from

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“…Although a role for the sleep-wake cycle in the pathogenesis of AD has been proposed previously [26,33,45,54] , this idea has received relatively little attention; however, it has become increasingly compelling in light of recent findings in human molecular and neuroimaging studies. Here we draw together several lines of previous work [1, 2, 8, 10, 12-14, 21, 33, 35-37, 39, 42, 43, 55-67] to outline a hypnic hypothesis of AD pathophysiology.…”

Section: A 'Hypnic Hypothesis' Of Admentioning

confidence: 99%

“…Manipulation of synaptic vesicle release affects β-amyloid levels in interstitial fluid, suggesting a direct mechanistic link [45] . Conversely, both the diurnal fluctuation of CSF β-amyloid levels and the sleep-wake cycle can be normalised by immunisation against β-amyloid-42 in transgenic mouse models of AD [33] . Melatonin has anti-fibrillary actions [31] and inhibits deposition of β-amyloid and development of cognitive deficits in mouse models of AD [23,27,28] .…”

Section: Evidence For the Hypothesis: Cellular And Molecular Links Bementioning

confidence: 99%

“…However, converging evidence drawn from molecular biology, sleep neuroscience [21][22][23][24][25][26][27][28][29][30][31][32][33][34] and clinical neurology [35][36][37][38][39][40][41][42] suggests that sleep may interact in diverse and important ways with the pathophysiology of AD. Ramifications of long-term disruption in the sleep-wake cycle could include synaptic overactivity and excitotoxicity [10,21,[43][44][45] , impaired synaptic pruning [46] , failure of synaptic scaling and homeostatic responses [19,20,27,[47][48][49][50][51] , transmission of pathogenic proteins (β-amyloid and tau) [9,15,16] , and disruption of neural circuitry in the vulnerable DMN [6,8,12,21,52,53] .…”

Section: Introductionmentioning

confidence: 99%

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P4–021: A hypnic hypothesis of Alzheimer's disease

Clark

Warren

2013

Alzheimer's & Dementia

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condition. Molecular biological, biochemical and neuroimaging studies have yielded a substantial body of data on the causes and evolution of AD [1][2][3][4][5] , whilst the concept of a vulnerable distributed brain network provides a framework for explaining how molecular events might scale up to a clinical phenotype [6][7][8][9] . It is increasingly clear that AD has a protracted prodromal phase prior to clinical onset during which potentially pathogenic factors could operate and might have cumulative effects [5] .On a biochemical level, synaptic alterations are hypothesised to play a key role in the pathogenesis of many neurodegenerative diseases, including AD [9][10][11] . Such alterations may promote the transfer of pathogenic molecular species (in particular, β-amyloid oligomers) leading to the diffusive spread of misfolded proteins (in particular, hyperphosphorylated tau) throughout a vulnerable, distributed brain network, the so-called 'default mode network' (DMN) that appears to be integral to the operation of the normal resting brain [12][13][14][15][16] . Most accounts of synaptic dysfunction in AD emphasise molecular and biochemical events impacting on synaptic physiology via a loss of structural integrity [11,17] . However, an alternative (and by no means mutually exclusive) possibility is the promotion of synaptic damage by altered patterns of synaptic activity and excitotoxicity [18] . A fundamental example of a pervasive, phasic alteration in synaptic activity is the circadian sleep-wake cycle, which is associated with profound changes in many aspects of cellular and synaptic function [19,20] . Key WordsSleep · Alzheimer's disease · Neurodegeneration · Default mode network Abstract Background: Understanding the pathophysiology of Alzheimer's disease (AD) is of fundamental importance for improved diagnosis, monitoring and ultimately, treatment. Objective: A role for the sleep-wake cycle in the pathogenesis of AD has been proposed, but remains to be worked out in detail. Methods: Here we draw together several lines of previous work to outline a 'hypnic hypothesis' of AD. Results: We propose that altered function of brainstem neuro transmitter pathways associated with sleep, promotes regio nally specific disintegration of a cortico-subcortical 'default mode' brain network that is selectively vulnerable in AD. Conclusion: The formation of a dynamic toxic state within this vulnerable network linked to sleep-wake disruption, would in turn lead to failure of synaptic repair, increased transmission of pathogenic misfolded proteins and a self-amplifying neurodegenerative process. We consider the evidence for this hypnic hypothesis and the implications that follow on from it.

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Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology

Cited by 503 publications

References 45 publications

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly

Translational profiling of hypocretin neurons identifies candidate molecules for sleep regulation

P4–021: A hypnic hypothesis of Alzheimer's disease

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