Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Polo I, 3004-504 Coimbra, Portugal.
Faculty of Medicine, University of Coimbra, Polo III, 3004-354 Coimbra, Portugal.
Int J Mol Sci. 2023 Jan 1;24(1):778. doi: 10.3390/ijms24010778.
ε4 allele (ApoE4) is the primary genetic risk factor for sporadic Alzheimer's disease (AD), expressed in 40-65% of all AD patients. ApoE4 has been associated to many pathological processes possibly linked to cognitive impairment, such as amyloid-β (Aβ) and tau pathologies. However, the exact mechanism underlying ApoE4 impact on AD progression is unclear, while no effective therapies are available for this highly debilitating neurodegenerative disorder. This review describes the current knowledge of ApoE4 interaction with mitochondria, causing mitochondrial dysfunction and neurotoxicity, associated with increased mitochondrial Ca and reactive oxygen species (ROS) levels, and it effects on mitochondrial dynamics, namely fusion and fission, and mitophagy. Moreover, ApoE4 translocates to the nucleus, regulating the expression of genes involved in aging, Aβ production, inflammation and apoptosis, potentially linked to AD pathogenesis. Thus, novel therapeutical targets can be envisaged to counteract the effects induced by ApoE4 in AD brain.
ε4 等位基因（ApoE4）是散发性阿尔茨海默病（AD）的主要遗传风险因素，约占所有 AD 患者的 40-65%。ApoE4 与许多可能与认知障碍相关的病理过程有关，如淀粉样蛋白-β（Aβ）和 tau 病理。然而，ApoE4 对 AD 进展的影响的确切机制尚不清楚，而对于这种高度致残的神经退行性疾病，尚无有效的治疗方法。本文综述了目前关于 ApoE4 与线粒体相互作用的知识，导致线粒体功能障碍和神经毒性，与线粒体钙和活性氧（ROS）水平升高以及线粒体动力学（融合和裂变）和线粒体自噬有关。此外，ApoE4 易位到细胞核，调节与 AD 发病机制相关的参与衰老、Aβ 产生、炎症和细胞凋亡的基因的表达。因此，可以设想新的治疗靶点来对抗 ApoE4 在 AD 大脑中引起的影响。
