Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Nat Neurosci. 2011 Jul 3;14(8):1023-32. doi: 10.1038/nn.2858.
The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.
淀粉样蛋白-β肽 Aβ42 已知是阿尔茨海默病中主要的淀粉样生成和致病因子。然而，在受影响个体的大脑中同样频繁发现的 Aβ43 的作用仍未解决。我们生成了携带致病性早老素-1 R278I 突变的敲入小鼠，该突变导致 Aβ43 的过度产生。纯合子是胚胎致死的，表明该突变涉及功能丧失。将淀粉样前体蛋白转基因小鼠与杂合突变小鼠杂交导致 Aβ43 升高、短期记忆受损和淀粉样-β病理学加速，这伴随着 Aβ43 在斑块核心中的明显积累，其生化组成与受影响个体大脑中观察到的相似。一致地，Aβ43 表现出更高的聚集倾向，并且比 Aβ42 更具神经毒性。其他致病性早老素突变也以与 Aβ42 相关的方式导致 Aβ43 的过度产生，以及与疾病发病年龄相关。这些发现表明，被忽视的 Aβ43 是一种具有强烈淀粉样生成、神经毒性和丰富体内的物质。
