@article{a923403028cf4a0fb653234b84a0e63b,
title = "Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures",
abstract = "Background: Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer's disease (AD) progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in older adults with obstructive sleep apnea. However, the precise underlying mechanisms remain unknown. This study was undertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, and accumulation; cognition; synaptic plasticity; neuronal network excitability; and gene expression profiles in a P301S human mutant tau mouse model of AD and related tauopathies. Methods: We exposed 4- to 4.5-month-old male P301S and wild-type mice to an 8-week CIH protocol (6-min cycle: 21% O2 to 8% O2 to 21% O2, 80 cycles per 8 hours during daytime) and assessed its effect on tau pathology and various AD-related phenotypic and molecular signatures. Age- and sex-matched P301S and wild-type mice were reared in normoxia (21% O2) as experimental controls. Results: CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phosphorylated 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. Conclusions: 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 obstructive sleep apnea in AD pathogenesis.",
keywords = "Alzheimer's disease, Chronic intermittent hypoxia, Cognition, Molecular signatures, Synaptic plasticity, Tau",
author = "Kazim, {Syed Faraz} and Abhijeet Sharma and Saroja, {Sivaprakasam R.} and Seo, {Joon Ho} and Larson, {Chloe S.} and Aarthi Ramakrishnan and Minghui Wang and Blitzer, {Robert D.} and Li Shen and Pe{\~n}a, {Catherine J.} and Crary, {John F.} and Shimoda, {Larissa A.} and Bin Zhang and Nestler, {Eric J.} and Pereira, {Ana C.}",
note = "Funding Information: This work was supported by funding from the National Institutes of Health (Grant Nos. R01AG064020 and R01AG063819 [to ACP]), Paul B. Beeson Emerging Leaders Career Development Award in Aging (Grant No. K76AG054772 [to ACP]), the BrightFocus Foundation (to ACP), the DANA Foundation (to ACP), the Alzheimer{\textquoteright}s Drug Discovery Foundation (to ACP), the Alzheimer{\textquoteright}s Association (to ACP), the Bernard L. Schwartz Award for Physician Scientist (to ACP), and seed money from the Icahn School of Medicine at Mount Sinai (ISMMS) (to ACP). Funding Information: This work was supported by funding from the National Institutes of Health (Grant Nos. R01AG064020 and R01AG063819 [to ACP]), Paul B. Beeson Emerging Leaders Career Development Award in Aging (Grant No. K76AG054772 [to ACP]), the BrightFocus Foundation (to ACP), the DANA Foundation (to ACP), the Alzheimer's Drug Discovery Foundation (to ACP), the Alzheimer's Association (to ACP), the Bernard L. Schwartz Award for Physician Scientist (to ACP), and seed money from the Icahn School of Medicine at Mount Sinai (ISMMS) (to ACP). SFK and ACP designed the experiments; SFK, AS, CSL, SRS, JHS, and CJP conducted experiments and acquired data; JFC, RDB, AR, LS, MW, BZ, and EJN provided materials and data analysis tools; SFK, AS, CSL, AR, LS, RDB, SRS, JHS, and ACP contributed to data analysis; SFK and ACP wrote the first version of the manuscript; SFK, AS, CSL, AR, RDB, LS, CJP, JFC, LAS, EJN, SRS, JHS, and ACP edited the manuscript. All authors read and approved the final version of the manuscript. We thank Mr. Mark Rowland, Mr. Brian Coy, Dr. Nathalie Zeitouni, Dr. Mike Montana, and Dr. Melissa L. Bates for informative discussions on the chronic intermittent hypoxia system setup; the Mount Sinai Neuropathology Brain Bank & Research CoRE for assistance with providing postmortem human Alzheimer's disease brain tissue; Ms. Yunn-Chyn Tung and Dr. Wen Hu for informative discussion on human Alzheimer's disease p-tau seeds preparation; Dr. Eric Nestler Lab members for assistance with behavioral studies and stereotaxic injections; Dr. Ali Sharma and Mr. Tomas Fanutza for assistance with in vitro electrophysiology; and Microscopy Core at ISMMS for technical assistance. The gene expression data discussed in this publication will be deposited in National Center for Biotechnology Information's Gene Expression Omnibus and are available in Supplement 2. All other relevant data are available in the main text or Supplement 1. The raw data files are available from the authors on reasonable request. The authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2021 Society of Biological Psychiatry",
year = "2022",
month = feb,
day = "15",
doi = "10.1016/j.biopsych.2021.02.973",
language = "English (US)",
volume = "91",
pages = "346--358",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "4",
}