Ding Jiuyang, Sun Baofei, Gao Yang, Gu Cihang, Zhang Jian, Wang Li, Zheng Jie, Xia Bing, Qi Xiaolan
School of Forensic Medicine, Guizhou Medical University, Guiyang, China.
Key Laboratory of Human Brain Bank for Functions and Diseases of Department of Education of Guizhou Province, Guizhou Medical University, Guiyang, China.
CNS Neurosci Ther. 2025 Aug;31(8):e70536. doi: 10.1111/cns.70536.
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.
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.
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.
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.
载脂蛋白ε4等位基因（APOE4）是动脉粥样硬化（AS）和神经退行性疾病（如阿尔茨海默病（AD））的常见危险因素，但在AS病理状态下，APOE4是否以及如何在大脑中诱导AD样神经病变仍不清楚。
通过结合AS患者的尸检大脑和APOE4基因敲入小鼠，我们研究了APOE4对AS大脑中tau蛋白及相关神经病理变化的影响。采用行为学和病理学观察来评估促进胆固醇转运对APOE4 AS小鼠的保护作用。
在此，我们发现APOE4携带者在AS尸检大脑中表现出较高的AD样磷酸化Tau（p-Tau）水平。在高脂饮食喂养的小鼠中敲入人类APOE4会诱发AS病理，并将AS与AD联系起来。APOE4增加了脑胆固醇含量，这可能会触发蛋白磷酸酶2A（PP2A）的降解。我们进一步证明胆固醇可促进PP2A B和PP2A C的泛素化，它们分别是PP2A的调节亚基和催化亚基，导致PP2A B和PP2A C通过泛素-蛋白酶体系统降解。PP2A B和PP2A C的减少导致大脑Tau蛋白在多个与AD相关的位点过度磷酸化。APOE4 AS小鼠同时表现出AD样表型，包括突触退化、血脑屏障破坏、神经胶质细胞激活和认知障碍。药理学上促进胆固醇转运可减轻APOE4 AS小鼠的神经病理变化。
总之，这些结果表明APOE4在将AS与Tau神经病理联系起来方面发挥了作用，这可能会增加AS患者患相关神经退行性疾病的风险。
