Iwatsubo T
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo.
Rinsho Shinkeigaku. 2000 Dec;40(12):1228-30.
The deposition of amyloid beta peptides (A beta) is one of the pathological hallmarks of Alzheimer's disease (AD) brains. A beta are composed of 40-42 amino acid peptides that are proteolytically cleaved from beta APP. The deposition as diffuse plaques of a species of A beta ending at the 42nd residue (A beta 42) is one of the earliest pathological changes of AD. Importantly, mutations in beta APP genes located in positions flanking the A beta sequences have been shown to cosegregate with the clinical manifestations of AD in a subset of familial AD (FAD) pedigrees. Moreover, mutations in presenilin (PS) 1 and 2, novel polytopic membrane proteins identified as causative molecules for the majority of FAD, also increase the production of A beta 42. These results support the notion that A beta (42) plays a key role in the cascadic development of AD. Recently, PS 1 and PS 2 are shown to be the catalytic subunits of gamma-secretase that cleave the intramembrane segments of beta APP and Notch. Future therapeutic approaches to reduce amyloid deposition, including inhibitors for beta- and gamma-secretases, as well as beta-amyloid vaccine therapy, raise high hopes towards the cure and prevention of AD, although the outcome thereof would be key to the consistency of amyloid cascade hypothesis.
β淀粉样肽（Aβ）的沉积是阿尔茨海默病（AD）大脑的病理特征之一。Aβ由40 - 42个氨基酸肽组成，这些肽是从β淀粉样前体蛋白（βAPP）经蛋白水解切割产生的。以第42位残基结尾的一种Aβ（Aβ42）以弥漫性斑块形式沉积是AD最早的病理变化之一。重要的是，位于Aβ序列侧翼位置的βAPP基因突变已被证明在一部分家族性AD（FAD）家系中与AD的临床表现共分离。此外，早老素（PS）1和2的突变，这两种新发现的多聚体膜蛋白被确定为大多数FAD的致病分子，也会增加Aβ42的产生。这些结果支持了Aβ（42）在AD的级联发展中起关键作用这一观点。最近，PS 1和PS 2被证明是γ-分泌酶的催化亚基，γ-分泌酶可切割βAPP和Notch的膜内片段。未来减少淀粉样蛋白沉积的治疗方法，包括β-和γ-分泌酶抑制剂以及β-淀粉样蛋白疫苗治疗，为AD的治愈和预防带来了很高的期望，尽管其结果对于淀粉样蛋白级联假说的一致性至关重要。
