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Chronic intermittent hypoxia enhances pathological tau seeding, propagation, and accumulation, and exacerbates Alzheimer’s-like memory and synaptic plasticity deficits and molecular signatures

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE169478 | GEO | 2021/03/24

REPOSITORIES: GEO

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Project description:Background and aims: Aortic dissection (AD) is a cardiovascular emergency with degeneration of the aortic media. Mounting evidence indicates obstructive sleep apnea (OSA) as an independent risk factor for AD development with unknown mechanisms. This study aims to establish a stable murine model of OSA-related AD (OSA-AD) and uncover the potential changes in gene transcripts in OSA-AD. Materials and methods: ApoE-/- mice were exposed to the chronic intermittent hypoxia (CIH) system combined with Ang II administration to establish the OSA-AD model. Pathological staining was performed to exhibit the physiological structure of the mouse aorta. The SBC mouse ceRNA microarray was used to identify significantly differentially expressed (DE) mRNAs, DE long-non-coding RNAs (DElncRNAs), and DE circular RNAs (DEcircRNAs) in OSA-AD tissues. Subsequently, bioinformatics analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and protein–protein interaction (PPI) analyses, was performed to evaluate the function of the significantly differentially expressed transcripts (DETs). The hub genes were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). Results: ApoE-/- mice exposed to CIH and Ang II showed a high ratio of aortic accident (73.33%) and significant aortic diameter dilatation (1.96 ± 0.175 mm). A total of 1,742 mRNAs, 2,625 lncRNAs, and 537 circRNAs were identified as DETs (LogFC ≥ 1.5 or ≤ –1.5, P < 0.05). GO and KEGG analyses demonstrated that the differentially expressed mRNAs (DEmRNAs) were most enriched in cell proliferation, migration, apoptosis, inflammation, and hypoxia-related terms, which are closely related to aortic structural homeostasis. The PPI network contained 609 nodes and 934 connections, the hub genes were highlighted with the CytoHubba plugin and confirmed by qRT-PCR in AD tissues. KEGG pathway analysis revealed that the cis-regulated genes of DElncRNAs and circRNAs-host genes were enriched in aortic structural homeostasis-related pathways. Conclusion: Our findings help establish a de novo OSA-AD animal model using ApoE-/- mice. Many DEmRNAs, DElncRNAs, and DEcircRNAs were screened for the first time in OSA-AD tissues. Our findings provide useful bioinformatics data for understanding the molecular mechanism of OSA-AD and developing potential therapeutic strategies for OSA-AD.

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Chronic intermittent hypoxia enhances pathological tau seeding, propagation, and accumulation, and exacerbates Alzheimer’s-like memory and synaptic plasticity deficits and molecular signatures

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