Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice

Jagirdar, Rohan; Fu, Chia-Hsuan; Park, Jin; Corbett, Brian; Seibt, Frederik; Beierlein, Michael; Chin, Jeannie

doi:10.1126/scitranslmed.abh4284

Cited by 20 publications

(10 citation statements)

References 85 publications

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“…For example, one night of sleep deprivation in humans significantly increased detectable Aβ levels in the brain (Shokri-Kojori et al, 2018), slow-wave sleep disruption increased Aβ levels in the CSF (Ju et al, 2017), and chronic sleep restriction in mouse AD models (Kang et al, 2009) or rats (Zhao et al, 2019) increased Aβ plaque accumulation. Conversely, pharmacologically or optogenetically improving sleep in mouse models of AD reduced the overall lifetime Aβ plaque burden (Jagirdar et al, 2021; Kang et al, 2009). Together, these observations have led to the proposal that sleep and Aβ dynamics create a positive feedforward cycle, wherein increases in wakefulness result in increased extracellular Aβ and aggregation, which then dysregulates sleep, further exacerbating the creation of pathogenic Aβ production (Ju et al, 2014; Roh et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

Özcan

Lim

Rihel

2022

Preprint

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Sleep-wake disturbances are among the earliest symptoms of Alzheimer's disease (AD) and contribute to disease severity. Since a major driver of AD— the accumulation of amyloid-beta (Aβ) in the brain— is modulated by sleep, a "vicious" feedforward cycle has been proposed in which Aβ buildup disrupts sleep, leading to more Aβ secretion and further worsening of sleep and AD. Consistent with this idea, mouse models of AD develop early sleep phenotypes, and sleep is acutely modulated by exogenous Aβ. However, these overexpression paradigms leave unclear whether endogenous Aβ signaling contributes to sleep regulation. To tackle this question, we generated loss of function mutations in the zebrafish orthologs of Amyloid Precursor Protein (APP) and monitored larval sleep behavior. Larvae with mutations in appa had reduced waking activity levels but normal sleep patterns, while larvae that lacked appb had reduced sleep due to an inability to maintain sleep bout durations. In addition, larvae exposed to the γ-secretase inhibitor DAPT, which inhibits Aβ production from APP, also have shorter sleep bouts at night. Although γ-secretase inhibition impacts the proteolytic cleavage of many proteins, appb mutants were insensitive to the sleep bout shortening effects of DAPT, suggesting that loss of γ-secretase dependent proteolytic cleavage products of Appb are responsible for the reduced sleep maintenance phenotypes. These results are consistent with a model in which endogenous Aβ directly modulates sleep in zebrafish and supports the idea that sleep disturbances may be a useful early-onset biomarker for AD.

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Section: Introductionmentioning

confidence: 99%

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

Özcan

Lim

Rihel

2022

Preprint

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“…Although the exact mechanism of sleep disturbance involved in cognitive impairment has not been fully determined. A growing number of studies have found that sleep disorders may lead to cognitive impairment and accelerate AD pathology, including increased Aβ deposition in the brain [42][43][44][45][46][47][48]. Our recent studies also showed that sleep deprivation induced peripheral Aβ transport dysfunction in young adults, and Aβ accumulation in the brain in rats [49,50].…”

Section: Discussionmentioning

confidence: 65%

Sleep disturbance is associated with mild cognitive impairment: a community population-based cross-sectional study

et al. 2022

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Background Sleep is conducive to the elimination of brain metabolites and the recovery of brain function. However, the relationship between sleep disturbance and Mild Cognitive Impairment is not fully been determined. Methods This was a community population-based cross-sectional study. A total of 1,443 participants from a village in the suburbs of Xi’an, China were enrolled in 2017. Sleep quality was evaluated using the Pittsburgh sleep quality index (PSQI), and sleep disturbance was defined as a PSQI score > 5. Mini-Mental State Examination (MMSE) was used to assess cognitive function and Mild Cognitive Impairment(MCI) was defined as the MMSE score less than cutoff values and meets the diagnostic criteria. Univariate and multivariate analyses were used to analyze the relationships between sleep disturbance and MCI. Results Among 1,443 subjects, 69(4.78%) had MCI, and 830 (57.52%) had sleep disturbance. In bivariate analysis, MCI was associated with sleep disturbance (ρ = 0.094, P<0.001). In the binary logistic regression, MCI was positively associated with the sleep disturbance (OR = 2.027, 95%CI = 1.112–3.698, P = 0.021). In the internal constitution of PSQI, MCI was negatively associated with the habitual sleep efficiency (OR = 0.447, 95%CI = 0.299–0.669, P < 0.001). Compared with waking up before or at 7 am, waking up after 7 am (OR = 0.555, 95%CI = 0.309–0.995, P = 0.048), or 8 am (OR = 0.296, 95%CI = 0.097–0.902, P = 0.032) was probably more likely to have normal cognition. However, people who slept more than 8 h a day might be more likely to suffer from MCI (OR = 5.560, 95%CI = 1.419–21.789, P = 0.014). Conclusion Sleep disturbance is associated with Mild Cognitive Impairment. However, the causal relationship between them is not clear. It needs to be further studied.

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“…In wild-type rats and mice overexpressing mutated human APP and PSEN1 , restricting sleep for 21 days increased Aβ deposits in the cortex 67,68 . Conversely, pharmaceutically or chemogenetically consolidating sleep in AD mouse models for 1–2 months delayed Aβ plaque formation 67,69 . Disrupted sleep is therefore likely to be a causal process in AD.…”

Section: Discussionmentioning

confidence: 99%

Behavioural pharmacology predicts disrupted signalling pathways and candidate therapeutics from zebrafish mutants of Alzheimer’s disease risk genes

Kroll,

Donnelly,

Özcan

et al. 2023

Preprint

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By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer’s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics.FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer’s risk genes tested. We developed an online tool,ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3,674 compounds. ZOLTAR successfully predicted thatsorl1mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep ofpresenilin-2knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.

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Restoring activity in the thalamic reticular nucleus improves sleep architecture and reduces Aβ accumulation in mice

Abstract: Chemogenetic stimulation of the thalamic reticular nucleus increases slow-wave sleep and reduces Aβ accumulation in rodents.

Cited by 20 publications

References 85 publications

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

“Genetic and chemical disruption of Amyloid Precursor Protein processing impairs zebrafish sleep maintenance”

Sleep disturbance is associated with mild cognitive impairment: a community population-based cross-sectional study

Behavioural pharmacology predicts disrupted signalling pathways and candidate therapeutics from zebrafish mutants of Alzheimer’s disease risk genes

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