Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation.
Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer's Disease Mutation.
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DOI：
10.1021/acschemneuro.5b00171
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发表时间：
2015-10-21
影响因子：
5
通讯作者：
Bowers MT
中科院分区：
文献类型：
--
作者：
Zheng X;Liu D;Roychaudhuri R;Teplow DB;Bowers MT
淀粉样β蛋白（Aβ）的寡聚状态似乎与阿尔茨海默病（AD）有因果关系。最近，淀粉样蛋白前体蛋白基因的两个家族性突变被描述，都导致Aβ中Ala2 （A2）的氨基酸替换。A2V突变可导致常染色体隐性早发性AD。有趣的是，杂合子对这种疾病的发展有一定的保护作用。A2T替代可以预防AD和非AD患者年龄相关的认知能力下降。在这里，我们使用离子迁移-质谱（IM-MS）来检查这些突变对Aβ组装的影响。这些研究揭示了每种肽的早期低聚物形成的不同组装途径。A2T Aβ42形成二聚体、四聚体和六聚体，但十二聚体的形成受到抑制。相比之下，对Aβ40的组装没有显著影响。A2V Aβ42也形成二聚体、四聚体和六聚体，但没有形成十二聚体。然而，与A2T或野生型（wt） a - β42不同，A2V a - β42形成三聚体。此外，A2V取代导致a - β40发生类似于wt a - β42的寡聚，形成二聚体、四聚体、六聚体和十二聚体。而wt Aβ40仅形成二聚体和四聚体。这些结果为理解这两种突变如何导致或预防AD提供了基础。他们还表明，除了经常讨论的中心疏水簇和c端外，a β n端在控制疾病易感性方面也起着关键作用。
Oligomeric states of the amyloid β-protein (Aβ) appear to be causally related to Alzheimer’s disease (AD). Recently, two familial mutations in the amyloid precursor protein gene have been described, both resulting in amino acid substitutions at Ala2 (A2) within Aβ. An A2V mutation causes autosomal recessive early onset AD. Interestingly, heterozygotes enjoy some protection against development of the disease. An A2T substitution protects against AD and age-related cognitive decline in non-AD patients. Here, we use ion mobility-mass spectrometry (IM-MS) to examine the effects of these mutations on Aβ assembly. These studies reveal different assembly pathways for early oligomer formation for each peptide. A2T Aβ42 formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast, no significant effects on Aβ40 assembly were observed. A2V Aβ42 also formed dimers, tetramers, and hexamers, but no dodecamers. However, A2V Aβ42 formed trimers, unlike A2T or wild type (wt) Aβ42. In addition, the A2V substitution caused Aβ40 to oligomerize similar to wt Aβ42, as evidenced by the formation of dimers, tetramers, hexamers, and dodecamers. In contrast, wt Aβ40 formed only dimers and tetramers. These results provide a basis for understanding how these two mutations lead to, or protect against, AD. They also suggest that the Aβ N-terminus, in addition to the oft discussed central hydrophobic cluster and C-terminus, can play a key role in controlling disease susceptibility.