阿尔茨海默病中的载脂蛋白E4和突触功能障碍：机制和治疗意义
Apolipoprotein E4 and synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic implications.
摘要(中文译文)
阿尔茨海默病（AD）以进行性认知功能下降为特征，而突触功能障碍与临床症状的相关性最为密切。载脂蛋白E ε4（ApoE4）等位基因是晚发性AD最强的遗传风险因素。除了在淀粉样蛋白β聚集和tau蛋白过度磷酸化中的作用外，ApoE4还通过扰乱脂质代谢、神经免疫调节、线粒体动力学和活动依赖性可塑性来破坏突触完整性。这些由ApoE4驱动的机制损害突触前囊泡运输，使突触后受体和支架网络（包括PSD-95、SynGAP和Shank3）失稳，并加速补体和微胶质细胞介导的突触修剪。总体而言，这些过程共同导致神经元回路失稳并驱动早期认知功能下降。在本综述中，我们综合了当前关于ApoE4损害突触功能的分子机制的证据，特别关注脂质微区不稳定、线粒体功能障碍以及突触后致密蛋白的崩溃。我们还讨论了增强突触韧性的治疗策略，包括调节谷氨酸能传递、恢复脂质稳态、增强神经营养信号传导以及调控微胶质细胞活性。在APOE ε4携带者中靶向突触保护有望成为一种减缓AD认知功能下降的疾病修饰方法。
Abstract
Alzheimer's disease (AD) is characterized by progressive cognitive decline, with synaptic dysfunction as the strongest correlate of clinical symptoms. The apolipoprotein E ε4 (ApoE4) allele is the most potent genetic risk factor for late-onset AD. Beyond its roles in amyloid-β aggregation and tau hyperphosphorylation, ApoE4 disrupts synaptic integrity by perturbing lipid metabolism, neuroimmune regulation, mitochondrial dynamics, and activity-dependent plasticity. These ApoE4-driven mechanisms impair presynaptic vesicle trafficking, destabilize postsynaptic receptor and scaffolding networks (including PSD-95, SynGAP, and Shank3), and accelerate complement- and microglia-mediated synaptic pruning. Collectively, these processes converge to destabilize neuronal circuits and drive early cognitive decline. In this review, we synthesize current evidence on the molecular mechanisms by which ApoE4 compromises synaptic function, with particular emphasis on lipid microdomain instability, mitochondrial failure, and the collapse of postsynaptic density proteins. We also discuss therapeutic strategies to enhance synaptic resilience, including modulation of glutamatergic transmission, restoration of lipid homeostasis, augmentation of neurotrophic signaling, and regulation of microglial activity. Targeting synaptic preservation in APOE ε4 carriers holds promise as a disease-modifying approach to mitigate cognitive decline in AD.
如何引用
AMA
Zhiying Yao, Ivan Steve Godje Godje, Bin Jiao, Lu Shen, Shilin Luo. Apolipoprotein E4 and synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic implications.. Ageing research reviews. 2026; doi:10.1016/j.arr.2026.103153.
APA
Zhiying Yao, Ivan Steve Godje Godje, Bin Jiao, Lu Shen, Shilin Luo (2026). Apolipoprotein E4 and synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic implications.. Ageing research reviews. https://doi.org/10.1016/j.arr.2026.103153
GB/T 7714
Zhiying Yao, Ivan Steve Godje Godje, Bin Jiao, Lu Shen, Shilin Luo. Apolipoprotein E4 and synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic implications.[J]. Ageing research reviews, 2026 doi:10.1016/j.arr.2026.103153.
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