Yang Qin, Chen Tingting, Li Shaofa, Yang Chengmin, Zheng Xingwu, Mao Sanying, Liu Ning, Mo Shenglong, Li Dengxing, Yang Meiling, Lu Zhicheng, Tang Lina, Huang Xiaorui, Liu Xia, Jian Chongdong, Yin Yixia, Shang Jingwei
Medical School, Jinan University, Guangzhou, Guangdong, China; Department of Neurology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China; Department of Neurology, Baise People's Hospital, Baise, Guangxi, China.
School of Basic Medicine, Guangdong Medical University, DongGuang, China.
Brain Res. 2025 Mar 1;1850:149416. doi: 10.1016/j.brainres.2024.149416. Epub 2024 Dec 20.
This study aimed to investigate the impact of chronic cerebral hypoperfusion (CCH) on cognitive function, amyloid-β (Aβ) deposition, cellular autophagy, and mitochondrial dynamics in an Alzheimer's disease (AD) mouse model, and to evaluate the intervention effects of autophagy modulation on these outcomes. Utilizing the APP/PS1 mouse model combined with CCH, we assessed cognitive function, Aβ deposition, and the expression levels of relevant proteins through behavioral tests and immunohistochemical analysis. Our findings revealed pronounced cognitive deficits and increased Aβ deposition in the AD + CCH group mice, along with upregulation of mitochondrial fission proteins (Drp1, Fis1) and downregulation of mitochondrial fusion proteins (Opa1, Mfn1), indicating a shift towards mitochondrial fission and promoting cell apoptosis. Additionally, alterations were observed in the expression levels of cellular autophagy-related proteins (LC3-II, P62), which were reversed by treatment with autophagic inhibitor 3-methyladenine (3-MA). Furthermore, the expression of mitochondrial autophagy-related proteins PINK1 and Parkin was affected, with 3-MA alleviating this effect. In summary, our study elucidates the complex interplay among cognitive decline, increased Aβ deposition, and mitochondrial dysfunction in the AD + CCH model, and suggests that modulating autophagy could be a potential therapeutic strategy for treating the AD + CCH model.
本研究旨在探讨慢性脑灌注不足（CCH）对阿尔茨海默病（AD）小鼠模型认知功能、淀粉样β蛋白（Aβ）沉积、细胞自噬和线粒体动力学的影响，并评估自噬调节对这些结果的干预作用。利用APP/PS1小鼠模型结合CCH，我们通过行为测试和免疫组织化学分析评估了认知功能、Aβ沉积以及相关蛋白的表达水平。我们的研究结果显示，AD + CCH组小鼠存在明显的认知缺陷和Aβ沉积增加，同时线粒体分裂蛋白（Drp1、Fis1）上调，线粒体融合蛋白（Opa1、Mfn1）下调，表明向线粒体分裂转变并促进细胞凋亡。此外，观察到细胞自噬相关蛋白（LC3-II、P62）的表达水平发生变化，而用自噬抑制剂3-甲基腺嘌呤（3-MA）处理可逆转这种变化。此外，线粒体自噬相关蛋白PINK1和Parkin的表达也受到影响，3-MA可减轻这种影响。总之，我们的研究阐明了AD + CCH模型中认知衰退、Aβ沉积增加和线粒体功能障碍之间的复杂相互作用，并表明调节自噬可能是治疗AD + CCH模型的一种潜在治疗策略。
