载脂蛋白E调控阿尔茨海默病病理的机制

Apolipoprotein E regulates the pathology of Alzheimer's disease

阿尔茨海默病(Alzheimer's disease,AD)的病理特征是淀粉样斑块(amyloid plaques)和神经原纤维缠结(neurofibrillary tangles,NFTs)的沉积。而淀粉样斑块的重要成分是β淀粉样蛋白(Aβ)。载脂蛋白E基因(APOE)是AD最主要的风险基因之一,其编码的载脂蛋白E(APOE),被认为与AD的多种致病过程有关。人类APOE有三种主要的等位基因:APOEɛ2、APOEɛ3和APOEɛ4。其中APOEɛ4可以促进小胶质细胞和星形胶质细胞的炎症反应和相关细胞因子的分泌,继而引发神经炎症。APOE还可直接与Aβ相互作用,促进其在不溶性纤维沉积物中的聚集和沉积。除了参与Aβ病理,来自星形胶质细胞和神经元的APOE4通过不同的方式,促进了tau蛋白的高度磷酸化以及病理性tau蛋白介导的神经元死亡和神经变性病变。此外,APOE4伴随着更多的补体激活导致的突触丢失。神经毒性APOE4片段可引起的线粒体功能障碍和血脑屏障(blood brain barrier,BBB)通透性的增加。髓样细胞-2上表达触发受体(Triggering receptor expressed on myeloid cell 2,TREM2)依赖途径上调的APOE转录,可诱导小胶质细胞参与的神经炎症反应。微生物菌群对神经炎症的调节也通过APOE依赖的方式。总之,APOE对AD的发生及进展产生重要的影响,以APOE/APOE受体或其聚合物以及其保护性突变等为靶点的治疗,可能为AD的治疗提供新的思路。

Alzheimer’s disease(AD)is pathologically characterized by the accumulation of amyloid plaques and the deposition of neurofibrillary tangles(NFTs).An important component of amyloid plaques isβamyloid protein(Aβ).Apolipoprotein E genotype(APOE)has been reported as the biggest genetic risk factor for AD and apolipoprotein E(APOE),the APOE gene-encoded protein,has been suggested to be involved in a variety of pathogenic processes of AD.Human APOE has three major allelic variants:APOEɛ2,APOEɛ3,and APOEɛ4.APOE alleles,especially APOEɛ4,promoted inflammatory response and secretion of related cytokines in microglia and astrocytes.APOE interacts with Aβand promotes its aggregation and deposition in insoluble fibrillar deposits.Beside the Aβpathology,APOE4 from astrocytes and neurons could facilitate tau phosphorylation,as well as tau-mediated neurodegeneration.In addition,APOE4 is accompanied by greater complement activation and subsequently loss of synapse.Mitochondrial alterations and an increase of blood-brain barrier(BBB)permeability could be caused by neurotoxic APOE4 fragments.In AD,a triggering receptor expressed on myeloid cell 2(TREM2)-dependent pathway could activate APOE transcription,which induces the activation of microglia.The regulation of neuroinflammation by microbial communities is also dependent on APOE.In conclusion,APOE has an important impact on the mechanisms of AD,and therapies targeting APOE/APOE receptors or polymers,as well as protective variants,may provide new ideas for the treatment of AD.