Ontology highlight
ABSTRACT:
PROVIDER: PRJNA835913 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19141677_1.fastq.gz | Fastqsanger.gz | |||
| SRR19141677_2.fastq.gz | Fastqsanger.gz | |||
| SRR19141678_1.fastq.gz | Fastqsanger.gz | |||
| SRR19141678_2.fastq.gz | Fastqsanger.gz | |||
| SRR19141679_1.fastq.gz | Fastqsanger.gz |
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Project description:Obstructive sleep apnea (OSA), characterized by sleep fragmentation and chronic intermittenthypoxia (CIH), is a risk factor for Alzheimer’s disease (AD) progression. Recent epidemiologicalstudies point to CIH as the best predictor of developing cognitive decline and AD in elderly withOSA. However, the precise underlying mechanism(s) remain unknown. The present study wasundertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, andaccumulation, cognition, synaptic plasticity, neuronal network excitability, and gene expressionprofiles in a P301S human mutant tau mouse model of AD and related tauopathies. We exposed 4-4.5-month-old, male, P301S and WT mice to an 8-week CIH protocol (6 min cycle:21% O 2 to 8% O 2 to 21% O 2 , 80 cycles per 8 h during daytime), and assessed its effect on taupathology and various AD-related phenotypic and molecular signatures. Age- and gender-matched P301S and WT mice were reared in normoxia (21% O 2 ) as experimental controls. CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phospho-tau load. CIH also exacerbated memory and synaptic plasticity deficits in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD-related pathogenic molecular signaling in P301S mice. CIH-induced increase in pathologic human tau seeding and spread and exacerbation of other AD- related impairments provide new insights into the role of CIH and OSA in AD pathogenesis.
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Project description:Impaired sleep is a common aspect of aging and often precedes the onset of Alzheimer's disease. Here, we compare the effects of sleep deprivation in young wild-type mice and their APP/PS1 littermates, a murine model of Alzheimer's disease. After 7 h of sleep deprivation, both genotypes exhibit an increase in EEG slow-wave activity. However, only the wild-type mice demonstrate an increase in the power of infraslow norepinephrine oscillations, which are characteristic of healthy non-rapid eye movement sleep. Notably, the APP/PS1 mice fail to enhance norepinephrine oscillations 24 h after sleep deprivation, coinciding with an accumulation of cerebral amyloid-β protein. Proteome analysis of cerebrospinal fluid and extracellular fluid further supports these findings by showing altered protein clearance in APP/PS1 mice. We propose that the suppression of infraslow norepinephrine oscillations following sleep deprivation contributes to increased vulnerability to sleep loss and heightens the risk of developing amyloid pathology in early stages of Alzheimer's disease.
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