Molecular Mechanisms of Alzheimer’s Disease Protection by the A673T Allele of Amyloid Precursor Protein
Molecular Mechanisms of Alzheimer’s Disease Protection by the A673T Allele of Amyloid Precursor Protein
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淀粉样前体蛋白 A673T 等位基因保护阿尔茨海默病的分子机制
DOI：
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Atwal
中科院分区：
文献类型：
--
作者：
Janice A. Maloney;Travis W. Bainbridge;Amy Gustafson;Shuo Zhang;Roxanne V Kyauk;Pascal;Steiner;M. Brug;Yichin Liu;J. Ernst;R. Watts;K. Jasvinder;Atwal
结果：A673T 通过减少催化周转来减少 BACE1 对 APP 的加工，并减少淀粉样蛋白-β (A β ) 1-42 聚集。结论：APP 通过减少 A β 的产生，并且还通过减少聚集。意义：A673T 保护性突变的生化性质有助于深入了解 AD 的发展。摘要 淀粉样前体蛋白 (APP) 基因的致病性突变已被描述为导致早发家族性阿尔茨海默病 (AD) 的原因。我们最近发现了一种罕见的 APP 变体，其编码残基 673 (A673T) 处的丙氨酸至苏氨酸取代，可防止 AD 的发展 (1)。 A673 残基位于 β 分泌酶识别序列内，并且是 A β 肽切割产物的一部分（A β 的位置 2）。我们之前证明，A673T 取代使 APP 成为 BACE1 切割的不太有利的底物。在后续研究中，我们证实 A673T APP 在转染的小鼠原代神经元和同基因人 iPSC 衍生神经元中显示出 BACE1 的裂解减少。使用生化方法，我们表明 A673T 取代通过 BACE1 酶调节 APP 的催化周转率 (V max )，而不影响 APP 底物对 BACE1 的亲和力 (K m )。我们还显示 A2T A β 肽的 A β 1-42 聚集水平降低，这一观察结果在 A β 1-40 肽中不保守。当以 1:9 A β 1-42 :A β 1-40 的比例组合以模拟生理相关混合物时，A2T 保留了聚集动力学减慢的趋势。小胶质细胞对突变型 A β 1-42 肽的摄取与其聚集水平相关。突变体 A β 肽的细胞毒性没有显着改变。总而言之，我们的研究结果表明，A673T（APP 的保护性等位基因）可重复减少 APP 的淀粉样蛋白形成过程，并轻度降低 A β 聚集。这些效应可能共同对 AD 风险产生叠加甚至协同影响。
Results: A673T reduces BACE1 processing of APP by decreasing catalytic turnover, and reduces amyloid- β (A β ) 1-42 aggregation. Conclusion: APP by reducing A β production, and also by reducing aggregation. Significance: The biochemical nature of the A673T protective mutation provides insight into AD development. ABSTRACT Pathogenic mutations in the Amyloid precursor protein (APP) gene have been described as causing early onset familial Alzheimer’s disease (AD). We recently identified a rare APP variant encoding an alanine-to-threonine substitution at residue 673 (A673T) that confers protection against development of AD (1). The A673 residue lies within the β -secretase recognition sequence, and is part of the A β peptide cleavage product (position 2 of A β ). We previously demonstrated that the A673T substitution makes APP a less favorable substrate for cleavage by BACE1. In follow-up studies, we confirm that A673T APP shows reduced cleavage by BACE1 in transfected mouse primary neurons and in isogenic human iPSC-derived neurons. Using a biochemical approach, we show that the A673T substitution modulates the catalytic turnover rate (V max ) of APP by the BACE1 enzyme, without affecting the affinity (K m ) of the APP substrate for BACE1. We also show a reduced level of A β 1-42 aggregation with A2T A β peptides, an observation not conserved in A β 1-40 peptides. When combined in a ratio of 1:9 A β 1-42 :A β 1-40 to mimic physiologically relevant mixtures, A2T retains a trend toward slowed aggregation kinetics. Microglial uptake of the mutant A β 1-42 peptides correlated with their aggregation level. Cytotoxicity of the mutant A β peptides was not dramatically altered. Taken together, our findings demonstrate that A673T, a protective allele of APP, reproducibly reduces amyloidogenic processing of APP and also mildly decreases A β aggregation. These effects could together have an additive or even synergistic impact on risk of developing AD.
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影响因子：
11.2
作者：
Fagan,AM;Younkin,LH;Morris,JC;Fryer,JD;Cole,TG;Younkin,SG;Holtzman,DM
通讯作者：
Holtzman,DM
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
56.9
作者：
E. Levy;M. Carman;I. Fernandez‐Madrid;M. Power;I. Lieberburg;S. V. van Duinen;G. Bots;W. Luyendijk;B. Frangione
通讯作者：
E. Levy;M. Carman;I. Fernandez‐Madrid;M. Power;I. Lieberburg;S. V. van Duinen;G. Bots;W. Luyendijk;B. Frangione
影响因子：
56.9
作者：
SUZUKI, N;CHEUNG, TT;YOUNKIN, SG
通讯作者：
YOUNKIN, SG
阿尔茨海默病。
影响因子：
5.7
作者：
Roses,AD
通讯作者：
Roses,AD