Life and Medical Sciences, Membrane Biology and Lipid Biochemistry Unit at the Kekulé-Institute, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany.
Prog Lipid Res. 2012 Oct;51(4):378-93. doi: 10.1016/j.plipres.2012.07.001. Epub 2012 Jul 23.
Alzheimer's disease is characterized by the progressive accumulation of extracellular deposits of the amyloid β-peptide (Aβ) and intraneuronal aggregates of the microtubule associated protein tau. Strong genetic, biochemical and cell biological evidence indicates critical roles of Aβ in the initiation of the pathogenic process, while tau might mediate its toxicity and neurodegeneration. Aβ is generated by proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases. Alternatively, APP can also be cleaved by α-secretase within the Aβ domain, thereby precluding subsequent production of Aβ. APP and the three secretases are integral membrane proteins and follow secretory and endocytic trafficking pathways. Thus, the membrane lipid composition could play important roles in trafficking and metabolism of Alzheimer's disease related proteins. Sphingolipids and especially complex gangliosides are abundant and characteristic components of neuronal membranes. Together with cholesterol, they confer unique characteristics to membrane domains, thereby regulating subcellular trafficking and signaling pathways. Thus, sphingolipids emerged to important modulators of biological processes including cell growth, differentiation, and senescence. Defects in sphingolipid catabolism are long known to cause severe lysosomal storage disorders, often characterized by neurological phenotypes. In recent studies it became evident that impaired sphingolipid metabolism could also be involved in Alzheimer's disease.
阿尔茨海默病的特征是细胞外淀粉样 β 肽 (Aβ) 沉积物的渐进积累和微管相关蛋白 tau 的神经元内聚集。强有力的遗传、生化和细胞生物学证据表明 Aβ 在发病过程的启动中起关键作用，而 tau 可能介导其毒性和神经退行性变。Aβ 通过β-和γ-分泌酶对淀粉样前体蛋白 (APP) 的蛋白水解加工产生。或者，APP 也可以被 Aβ 结构域内的α-分泌酶切割，从而阻止随后 Aβ 的产生。APP 和三种分泌酶都是整合膜蛋白，并遵循分泌和内吞运输途径。因此，膜脂质组成可能在阿尔茨海默病相关蛋白的运输和代谢中发挥重要作用。鞘脂类，特别是复杂的神经节苷脂，是神经元膜中丰富且具有特征的成分。它们与胆固醇一起赋予膜域独特的特性，从而调节细胞内运输和信号通路。因此，鞘脂类成为包括细胞生长、分化和衰老在内的许多生物学过程的重要调节剂。长期以来，人们一直知道鞘脂类代谢缺陷会导致严重的溶酶体贮积症，这些疾病通常表现出神经表型。最近的研究表明，鞘脂代谢受损也可能与阿尔茨海默病有关。
