Yu Zhong-Yuan, Liu Xiao-Yu, Li Qiong-Yan, Tuo Jin-Mei, Tan Qi, Liu Zhi-Hao, Yuan Zi-Yu, Zeng Ru, Zhao Yang, Li Jiang-Hui, Bai Yu-Di, Zeng Gui-Hua, Chen Dong-Wan, Bu Xian-Le, Jin Wang-Sheng, Wang Yan-Jiang
Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Institute of Brain and Intelligence, Army Medical University (Third Military Medical University), Chongqing, China.
Aging Cell. 2025 Sep 4:e70205. doi: 10.1111/acel.70205.
Apolipoprotein E4 (APOE4) is a significant risk for both familial Alzheimer's disease (AD) and sporadic AD with elusive mechanisms. Previous studies mainly focused on the role of APOE4 in familial AD, with less attention to sporadic AD. Our previous study demonstrated that blood cell-derived amyloid-β (Aβ) can enter the brain and induce AD-like pathologies, providing a novel animal model to study sporadic AD to a certain extent. The impacts of APOE4 on Alzheimer-like pathologies and cognitive deficits induced by blood-derived Aβ remain unknown. In the present study, we found that APOE4 prompted the entry of blood Aβ into the brain. APOE4 recipient mice showed impaired integrity of the blood-brain barrier and higher Aβ levels in the brain after transplantation of bone marrow cells from APP/PS1•APOE4 mice. In addition, we observed that the APOE4 recipient mice displayed aggravated tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits at the age of 12 months. Our study demonstrates that APOE4 is capable of facilitating the entry of blood-derived Aβ into the brain and enhancing the AD-like pathologies triggered by blood-derived Aβ. Our findings provide a possible way by which APOE4 elevates the risk of sporadic AD.
载脂蛋白E4（APOE4）是家族性阿尔茨海默病（AD）和散发性AD的重要风险因素，但其机制尚不清楚。以往的研究主要集中在APOE4在家族性AD中的作用，而对散发性AD的关注较少。我们之前的研究表明，血细胞衍生的淀粉样β蛋白（Aβ）可以进入大脑并诱发AD样病理变化，在一定程度上为研究散发性AD提供了一种新的动物模型。APOE4对血液来源的Aβ诱导的阿尔茨海默样病理变化和认知缺陷的影响尚不清楚。在本研究中，我们发现APOE4促使血液中的Aβ进入大脑。在移植了来自APP/PS1•APOE4小鼠的骨髓细胞后，APOE4受体小鼠的血脑屏障完整性受损，大脑中的Aβ水平升高。此外，我们观察到APOE4受体小鼠在12个月大时出现tau蛋白过度磷酸化加剧、神经元变性、神经炎症和行为缺陷。我们的研究表明，APOE4能够促进血液来源的Aβ进入大脑，并增强由血液来源的Aβ引发的AD样病理变化。我们的研究结果为APOE4增加散发性AD风险提供了一种可能的途径。
