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Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures

  • Author Footnotes
    1 SFK, AS, and SRS contributed equally to this work.
    Syed Faraz Kazim
    Footnotes
    1 SFK, AS, and SRS contributed equally to this work.
    Affiliations
    Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 SFK, AS, and SRS contributed equally to this work.
    Abhijeet Sharma
    Footnotes
    1 SFK, AS, and SRS contributed equally to this work.
    Affiliations
    Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 SFK, AS, and SRS contributed equally to this work.
    Sivaprakasam R. Saroja
    Footnotes
    1 SFK, AS, and SRS contributed equally to this work.
    Affiliations
    Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Joon Ho Seo
    Affiliations
    Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Chloe S. Larson
    Affiliations
    Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Aarthi Ramakrishnan
    Affiliations
    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Minghui Wang
    Affiliations
    Mount Sinai Center for Transformative Disease Modeling, Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Robert D. Blitzer
    Affiliations
    Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Li Shen
    Affiliations
    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Catherine J. Peña
    Affiliations
    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • John F. Crary
    Affiliations
    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Pathology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, New York

    Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Larissa A. Shimoda
    Affiliations
    Department of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Bin Zhang
    Affiliations
    Mount Sinai Center for Transformative Disease Modeling, Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Eric J. Nestler
    Affiliations
    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Ana C. Pereira
    Correspondence
    Address correspondence to Ana C. Pereira, M.D.
    Affiliations
    Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York

    Department of Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, New York
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  • Author Footnotes
    1 SFK, AS, and SRS contributed equally to this work.

      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

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