Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
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DOI：
10.1038/ncomms3246
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发表时间：
2013-08-01
影响因子：
16.6
通讯作者：
Fraering, Patrick C.
中科院分区：
文献类型：
--
作者：
Dimitrov, Mitko;Alattia, Jean-Rene;Fraering, Patrick C.
淀粉样前体蛋白（APP）中的病理性氨基酸取代和化学γ-分泌酶调节剂影响γ-分泌酶复合物对APP的加工和淀粉样β肽A β 42的产生，其积累被认为是阿尔茨海默病的病因。在这里，我们证明了在APP的跨膜结构域的突变，导致侵略性早发性家族性阿尔茨海默病影响γ-和ε-裂解位点，通过提高A β 42/40的比例和抑制AICD 50 -99的生产，两个生理APP胞内结构域（ICD）之一。这与γ-分泌酶调节剂形成鲜明对比，γ-分泌酶调节剂将A β 42的产生向较短的A β 38转移，但明确地保留了ε位点和APP-和Notch-ICD的产生。分子模拟表明，家族性阿尔茨海默病突变调节APP跨膜结构域的灵活性及其γ位点的呈递，同时修饰ε位点的溶剂化。
Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical gamma-secretase modulators affect the processing of APP by the gamma-secretase complex and the production of the amyloid-beta peptide A beta 42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both gamma- and epsilon-cleavage sites, by raising the A beta 42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to gamma- secretase modulators, which shift A beta 42 production towards the shorter A beta 38, but unequivocally spare the epsilon-site and APP- and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its gamma- site, modifying at the same time, the solvation of the epsilon-site.