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

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.

阻塞性睡眠呼吸暂停（Obstructive Sleep Apnea, OSA）以睡眠碎片化与慢性间歇性低氧（Chronic Intermittent Hypoxia, CIH）为特征，是阿尔茨海默病（Alzheimer Disease, AD）进展的危险因素。近年流行病学研究表明，CIH是老年OSA患者发生认知衰退与AD的最佳预测因子。然而，其确切的潜在机制仍未阐明。本研究旨在评估CIH对P301S人突变tau蛋白阿尔茨海默病及相关tau病变小鼠模型中，病理性人tau蛋白播种、扩散、聚集，认知功能、突触可塑性、神经元网络兴奋性以及基因表达谱的影响。我们将4~4.5月龄的雄性P301S小鼠与野生型（Wild Type, WT）小鼠暴露于为期8周的CIH造模方案中（循环周期6分钟：21%氧气→8%氧气→21%氧气，日间8小时内完成80个循环），并评估其对tau蛋白病理以及多种AD相关表型与分子特征的影响。年龄与性别匹配的P301S小鼠及WT小鼠饲养于常氧（21%氧气）环境中，作为实验对照。CIH可显著增强P301S小鼠体内病理性人tau蛋白的播种能力，并使其在连通脑环路中扩散；同时还可增加磷酸化tau蛋白（phosphorylated tau, phospho-tau）负荷。CIH还会加重P301S小鼠的记忆与突触可塑性损伤。但CIH对这些小鼠的癫痫易感性与网络过度兴奋性无显著影响。最后，CIH会加剧P301S小鼠体内AD相关的病理性分子信号通路激活。CIH诱导的病理性人tau蛋白播种与扩散增强，以及其他AD相关损伤的加重，为阐明CIH与OSA在AD发病机制中的作用提供了新的见解。