De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, Annaert W, Van Broeckhoven C, De Strooper B
Laboratory of Neurogenetics, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
Hum Mol Genet. 2001 Aug 1;10(16):1665-71. doi: 10.1093/hmg/10.16.1665.
Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.
淀粉样前体蛋白（APP）释放淀粉样β蛋白（Aβ）需要β-和γ-分泌酶的切割，并且在阿尔茨海默病（AD）发病机制中起关键作用。导致家族性AD的APP基因错义突变聚集在β-、α-和特定的γ-分泌酶切割位点周围。我们在原代神经元中系统地比较了一系列紧邻γ-分泌酶切割位点的临床APP突变（其中两个以前未被表征）对APP加工的影响。我们证实并扩展了先前的观察结果，表明所有这些突变（T714I、V715M、V715A、I716V、V717I和V717L）都会影响γ-分泌酶的切割，导致Aβ42与Aβ40的相对比例增加。利用这些扩展的APP突变系列，我们能够证明这些比例与不同家族中疾病发病年龄之间呈负相关。此外，一部分突变导致APP C末端片段的积累，表明这些突变也影响APP C末端片段的稳定性。然而，这些片段不太可能对疾病进程有显著贡献。
