Amyloid-Beta (Aβ) D7H Mutation Increases Oligomeric Aβ42 and Alters Properties of Aβ-Zinc/Copper Assemblies

Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP mutation, located within the Aβ sequence (AβD7H), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn2+ or Cu2+, AβD7H aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a “double punch” effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn2+ and Cu2+ in the etiology of AD.

与家族性阿尔茨海默病（familial Alzheimer's disease, AD）相关的淀粉样前体蛋白（amyloid precursor protein, APP）突变通常会导致β淀粉样蛋白（amyloid β-protein, Aβ）水平升高或聚集。本研究在一个早发性AD的台湾家系中鉴定出一种位于Aβ序列内的新型APP突变（AβD7H），并探究了该突变的致病性。细胞与生化分析结果显示，该突变可提升Aβ生成量、升高Aβ42/40比值，并延长Aβ42寡聚体的存在状态，同时伴随更高的神经毒性。由于D7H突变型Aβ多了一个组氨酸（histidine）这一金属离子配位残基，我们推测该突变可能增强Aβ对金属离子的易感性。当与Zn2+或Cu2+共孵育时，AβD7H会聚集为低分子量寡聚体。综上，D7H突变可通过对Aβ生成与聚集过程的“双重打击”效应参与阿尔茨海默病的病理进程。尽管该突变的致病本质仍需进一步验证，但本研究结果提示，Aβ的N端区域可调控APP加工与Aβ聚集，并为Zn2+和Cu2+在阿尔茨海默病病因学中的重要性提供了遗传学依据。