APOE4通过胆固醇诱导的磷酸酶降解在动脉粥样硬化中加剧脑Tau病理

IF 5 1区 医学 Q1 NEUROSCIENCES
Jiuyang Ding, Baofei Sun, Yang Gao, Cihang Gu, Jian Zhang, Li Wang, Jie Zheng, Bing Xia, Xiaolan Qi
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引用次数: 0

摘要

载脂蛋白epsilon4等位基因(APOE4)是动脉粥样硬化(AS)和阿尔茨海默病(AD)等神经退行性疾病的常见危险因素,但APOE4是否以及如何在AS病理的大脑中诱导AD样神经病变尚不清楚。方法结合死后AS脑组织和APOE4敲入小鼠,研究APOE4对AS脑组织tau蛋白及相关神经病理改变的影响。通过行为学和病理学观察来评价促进胆固醇转运对APOE4 AS小鼠的保护作用。我们发现APOE4携带者在AS死后大脑中表现出更高的ad样磷酸化Tau (p-Tau)水平。敲入高脂饮食小鼠的人APOE4诱导AS病理和AS与AD的耦合。APOE4促进脑内胆固醇含量,可触发蛋白磷酸酶2A (PP2A)降解。我们进一步证明胆固醇可以促进PP2A的调控亚基PP2A B和催化亚基PP2A C的泛素化,通过泛素-蛋白酶体系统导致PP2A B和PP2A C降解。PP2A B和PP2A C的减少导致大脑Tau在多个ad相关位点过度磷酸化。APOE4 AS小鼠表现出ad样表型,包括突触变性、血脑屏障破坏、神经胶质激活和认知障碍同时发生。药理学上促进胆固醇转运可减轻APOE4 AS小鼠的神经病变。综上所述,这些结果提示APOE4在AS与Tau神经病理的联系中起作用,这可能增加AS患者相关神经退行性疾病的风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

APOE4 Exacerbates Cerebral Tau Pathology Through Cholesterol-Induced Degradation of Phosphatase in Atherosclerosis

APOE4 Exacerbates Cerebral Tau Pathology Through Cholesterol-Induced Degradation of Phosphatase in Atherosclerosis

Background

Apolipoprotein epsilon4 allele (APOE4) is a common risk factor for atherosclerosis (AS) and neurodegenerative diseases like Alzheimer's disease (AD), but whether and how APOE4 induces AD-like neuropathies in the brain of AS pathology remains poorly characterized.

Methods

By combining postmortem AS human brains and APOE4 knock-in mice, we examined the effects of APOE4 on tau and related neuropathological changes in the brain of AS. Behavioral and pathological observations were used to evaluate the protective effects of facilitating cholesterol transport in APOE4 AS mice.

Results

Here, we showed that APOE4 carriers exhibited higher AD-like phosphorylated Tau (p-Tau) levels in AS postmortem brains. Knocking in human APOE4 in high fat diet-fed mice induced AS pathology and coupled AS and AD. APOE4 promoted cerebral cholesterol content, which could trigger protein phosphatase 2A (PP2A) degradation. We further demonstrated cholesterol could facilitate the ubiquitination of PP2A B and PP2A C, which were regulatory and catalytic subunits of PP2A respectively, leading to PP2A B and PP2A C degradation through the ubiquitin-proteasome system. Reduced PP2A B and PP2A C resulted in cerebral Tau hyperphosphorylated at multiple AD-associated sites. The APOE4 AS mice exhibited an AD-like phenotype, including synaptic degeneration, blood-brain barrier breakdown, glial activation, and cognitive impairment simultaneously. Pharmacologically facilitating cholesterol transport alleviated neuropathologies in APOE4 AS mice.

Conclusion

Altogether, these results suggested a role of the APOE4 in linking AS with Tau neuropathology, which might increase the risk of related neurodegenerative diseases for AS patients.

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来源期刊
CNS Neuroscience & Therapeutics
CNS Neuroscience & Therapeutics 医学-神经科学
CiteScore
7.30
自引率
12.70%
发文量
240
审稿时长
2 months
期刊介绍: CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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