Syed Faraz Kazim1, Abhijeet Sharma1, Sivaprakasam R Saroja1, Joon Ho Seo1, Chloe S Larson1, Aarthi Ramakrishnan2, Minghui Wang3, Robert D Blitzer4, Li Shen2, Catherine J Peña2, John F Crary5, Larissa A Shimoda6, Bin Zhang3, Eric J Nestler2, Ana C Pereira7. 1. 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. 2. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 3. 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. 4. 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. 5. 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. 6. Department of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 7. 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. Electronic address: ana.pereira@mssm.edu.
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.
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.
Authors: Peter T Nelson; Irina Alafuzoff; Eileen H Bigio; Constantin Bouras; Heiko Braak; Nigel J Cairns; Rudolph J Castellani; Barbara J Crain; Peter Davies; Kelly Del Tredici; Charles Duyckaerts; Matthew P Frosch; Vahram Haroutunian; Patrick R Hof; Christine M Hulette; Bradley T Hyman; Takeshi Iwatsubo; Kurt A Jellinger; Gregory A Jicha; Enikö Kövari; Walter A Kukull; James B Leverenz; Seth Love; Ian R Mackenzie; David M Mann; Eliezer Masliah; Ann C McKee; Thomas J Montine; John C Morris; Julie A Schneider; Joshua A Sonnen; Dietmar R Thal; John Q Trojanowski; Juan C Troncoso; Thomas Wisniewski; Randall L Woltjer; Thomas G Beach Journal: J Neuropathol Exp Neurol Date: 2012-05 Impact factor: 3.685
Authors: Li Liu; Valerie Drouet; Jessica W Wu; Menno P Witter; Scott A Small; Catherine Clelland; Karen Duff Journal: PLoS One Date: 2012-02-01 Impact factor: 3.240
Authors: Syed F Kazim; Shih-Chieh Chuang; Wangfa Zhao; Robert K S Wong; Riccardo Bianchi; Khalid Iqbal Journal: Front Aging Neurosci Date: 2017-03-24 Impact factor: 5.750
Authors: Thomas E Cope; Timothy Rittman; Robin J Borchert; P Simon Jones; Deniz Vatansever; Kieren Allinson; Luca Passamonti; Patricia Vazquez Rodriguez; W Richard Bevan-Jones; John T O'Brien; James B Rowe Journal: Brain Date: 2018-02-01 Impact factor: 13.501
Authors: Alexandria B Marciante; John Howard; Mia N Kelly; Juan Santiago Moreno; Latoya L Allen; Elisa J Gonzalez-Rothi; Gordon S Mitchell Journal: J Appl Physiol (1985) Date: 2022-07-21
Authors: Damian M Bailey; Anthony R Bain; Ryan L Hoiland; Otto F Barak; Ivan Drvis; Christophe Hirtz; Sylvain Lehmann; Nicola Marchi; Damir Janigro; David B MacLeod; Philip N Ainslie; Zeljko Dujic Journal: J Cereb Blood Flow Metab Date: 2022-01-21 Impact factor: 6.960