Ageing Research Reviews ( IF 13.1 ) Pub Date : 2019-12-28 , DOI: 10.1016/j.arr.2019.101006 B D Arbo 1 , L R Cechinel 2 , R P Palazzo 3 , I R Siqueira 4
Alzheimer’s Disease (AD) is characterized by progressive loss of cognitive abilities; senile plaques represent the major histopathological findings. Amyloid precursor protein (APP) processing machinery, and its product amyloid-beta (Aβ) peptide, have been found in extracellular vesicles (EVs), specifically exosomes, which allows for Aβ peptide aggregation and subsequent senile plaques deposition. We review the APP processing imbalance in EVs, autophagic and endosomal pathways in AD. Increased intraluminal vesicle (ILV) production and exosome release appear to counteract the endosomal dysfunction of APP processing; however, this process results in elevated amyloidogenic processing of APP and augmented senile plaque deposition. Several players related to APP processing and dysfunctional endosomal-lysosomal-exosomal (and other EVs) pathway are described, and the interconnected systems are discussed. The components Arc, p75, Rab11 and retromer complex emerge as candidates for key convergent mechanisms that lead to increased EVs loaded with APP machinery and Aβ levels, in atrophy and damage of basal forebrain cholinergic neurons in AD.
中文翻译:
内体功能障碍影响细胞外囊泡释放:在Aβ病理学中的核心作用。
阿尔茨海默氏病(AD)的特征在于认知能力的逐步丧失。老年斑代表主要的组织病理学发现。淀粉样前体蛋白(APP)加工机械及其产物淀粉样-β(Aβ)肽已在细胞外囊泡(EV)中,特别是外来体中被发现,从而允许Aβ肽聚集和随后的老年斑沉积。我们审查了电动汽车,自噬和内体途径在AD中的APP处理不平衡。腔内囊泡(ILV)产生的增加和外泌体的释放似乎可以抵消APP加工的内体功能障碍。但是,该过程导致APP的淀粉样蛋白生成过程增加,并且老年斑沉积增加。描述了与APP处理和功能失常的内体-溶酶体-外泌体(和其他EV)途径有关的几个参与者,并讨论了相互连接的系统。组件Arc,p75,Rab11和Retromer Complex成为关键收敛机制的候选物,这些机制导致AD中基础前脑胆碱能神经元的萎缩和损伤,导致电动汽车增加了APP机械和Aβ水平。