β-Amyloid Precursor Protein Mutants Respond to γ-Secretase Modulators
β-Amyloid Precursor Protein Mutants Respond to γ-Secretase Modulators
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DOI：
10.1074/jbc.m110.103283
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发表时间：
2010-06-04
影响因子：
4.8
通讯作者：
Steiner, Harald
中科院分区：
文献类型：
--
作者：
Page, Richard M.;Gutsmiedl, Amelie;Steiner, Harald
β-淀粉样蛋白前体蛋白（APP）的β-和γ-分泌酶裂解导致的淀粉样蛋白β-肽（A β）的42-氨基酸变体的致病性产生被认为是阿尔茨海默病（AD）的病因。通过γ-分泌酶调节剂（GSMs）降低A β（42）的产生是治疗AD的一种有希望的方法。GSM的作用机制尚未完全了解。此外，GSM是否靶向A β结构域是有争议的。为了进一步了解GSMs的作用模式和γ-分泌酶的切割机制，我们分析了位于A β结构域周围或内部的APP跨膜结构域不同位置的突变对GSMs的反应。我们发现，γ-分泌酶切割位点域的A β（42）增加家族性AD突变对A β（42）降低的GSM反应强烈，特别是对有效化合物GSM-1，无论产生的A β（42）的量如何。因此，我们预计在APP的γ-分泌酶切割位点携带突变的家族性AD患者应该对基于GSM的治疗方法有反应。该区域的系统性苯丙氨酸扫描诱变揭示了对GSM-1的高容许性，并证明了GSM作用的复杂机制，因为除了A β（42）之外，其他A β种类（A β（41），A β（39））也可以降低。此外，某些突变同时增加了A β（42）和较短的肽A β（38），这表明这些A β物种的蛋白质-产物关系并不普遍。最后，与A β（42）生成（Gly-29，Gly-33）和潜在的GSM结合（Lys-28）有关的拟定GSM结合位点中的残基突变也对GSM有反应，这一发现可能质疑APP底物靶向GSM。
Pathogenic generation of the 42-amino acid variant of the amyloid beta-peptide (A beta) by beta- and gamma-secretase cleavage of the beta-amyloid precursor protein (APP) is believed to be causative for Alzheimer disease (AD). Lowering of A beta(42) production by gamma-secretase modulators (GSMs) is a hopeful approach toward AD treatment. The mechanism of GSM action is not fully understood. Moreover, whether GSMs target the A beta domain is controversial. To further our understanding of the mode of action of GSMs and the cleavage mechanism of gamma-secretase, we analyzed mutations located at different positions of the APP transmembrane domain around or within the A beta domain regarding their response to GSMs. We found that A beta(42)-increasing familial AD mutations of the gamma-secretase cleavage site domain responded robustly to A beta(42)-lowering GSMs, especially to the potent compound GSM-1, irrespective of the amount of A beta(42) produced. We thus expect that familial AD patients carrying mutations at the gamma-secretase cleavage sites of APP should respond to GSM-based therapeutic approaches. Systematic phenylalanine-scanning mutagenesis of this region revealed a high permissiveness to GSM-1 and demonstrated a complex mechanism of GSM action as other A beta species (A beta(41), A beta(39)) could also be lowered besides A beta(42). Moreover, certain mutations simultaneously increased A beta(42) and the shorter peptide A beta(38), arguing that the proposed precursor-product relationship of these A beta species is not general. Finally, mutations of residues in the proposed GSM-binding site implicated in A beta(42) generation (Gly-29, Gly-33) and potentially in GSM-binding (Lys-28) were also responsive to GSMs, a finding that may question APP substrate targeting of GSMs.