Potent amyloidogenicity and pathogenicity of Aβ43
Potent amyloidogenicity and pathogenicity of Aβ43
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DOI：
10.1038/nn.2858
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发表时间：
2011-08-01
影响因子：
25
通讯作者：
Saido, Takaomi C.
中科院分区：
文献类型：
--
作者：
Saito, Takashi;Suemoto, Takahiro;Saido, Takaomi C.
已知淀粉样β肽A β 42是阿尔茨海默病中的主要淀粉样蛋白生成剂和致病剂。然而，A β 43在受影响个体的大脑中同样频繁地被发现，它的作用仍然没有得到解决。我们产生了含有致病性早老素-1 R278 I突变的基因敲入小鼠，该突变导致A β 43过度产生。纯合性是胚胎致死的，表明突变涉及功能丧失。将淀粉样前体蛋白转基因小鼠与杂合突变小鼠杂交，导致A β 43升高，短期记忆受损和淀粉样蛋白-b病理加速，这伴随着A β 43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，A β 43显示出更高的聚集倾向，并且比A β 42更具神经毒性。其他致病性早老素突变也导致A β 43的过度产生，其方式与A β 42和疾病发作的年龄相关。这些发现表明，A β 43，一个被忽视的物种，是潜在的淀粉样蛋白，神经毒性和丰富的体内。
The amyloid-beta peptide A beta 42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of A beta 43, 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 A beta 43. 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 A beta 43, impairment of short-term memory and acceleration of amyloid-b pathology, which accompanied pronounced accumulation of A beta 43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, A beta 43 showed a higher propensity to aggregate and was more neurotoxic than A beta 42. Other pathogenic presenilin mutations also caused overproduction of A beta 43 in a manner correlating with A beta 42 and with the age of disease onset. These findings indicate that A beta 43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.