Synthesis, aggregation, neurotoxicity, and secondary structure of various Aβ1-42 mutants of familial Alzheimer's disease at positions 21-23
Synthesis, aggregation, neurotoxicity, and secondary structure of various Aβ1-42 mutants of familial Alzheimer's disease at positions 21-23
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DOI：
10.1016/s0006-291x(02)00430-8
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发表时间：
2002-05-31
影响因子：
3.1
通讯作者：
Shirasawa, T
中科院分区：
文献类型：
--
作者：
Murakami, K;Irie, K;Shirasawa, T
淀粉样β蛋白（Amyloidbeta，Abeta）沉积引起的脑淀粉样血管病（Cerebralamyloidangiopathy，CAA）是阿尔茨海默病（Alzheimer 'sdisease，AD）的重要病理特征，尤其是家族性阿尔茨海默病（FAD），包括Dutch型遗传性脑出血伴淀粉样变性。Abeta主要由40-和42-mer肽（Abeta 1 -40和Abeta 1 -42）组成，其积聚在AD脑的老年斑中，并对培养的神经细胞显示神经毒性。我们合成了与报道的FAD相关的所有Abeta 1 -42变体形式，如A21 G（佛兰芒语）、E22 Q（荷兰语）、E22 K（意大利语）、E22 G（北极语）和D23 N（爱荷华州）沿着三种通过一点错义突变的潜在突变体（E22 A、E22 D和E22 V），并以高纯度形式检测了它们在PC 12细胞中的聚集能力和神经毒性。在位置22和23的突变体显示出强大的聚集能力和神经毒性，而潜在的突变体没有，表明在位置22和23的Abeta 1 -42突变体在荷兰，意大利，北极，和爱荷华州的FAD型中发挥关键作用。然而，佛兰芒型FAD需要替代的解释，除了相应的Abeta 1 -42突变体的聚集和神经毒性。(C)2002 Elsevier Science（美国）。All rights reserved.
Cerebral amyloid angiopathy (CAA) due to amyloid beta (Abeta) deposition is a key pathological feature of Alzheimer's disease (AD), especially in some form of familial Alzheimer's disease (FAD) including hereditary cerebral hemorrhage with amyloidosis-Dutch type. Abeta mainly consists of 40- and 42-mer peptides (Abeta1-40 and Abeta1-42), which accumulate in senile plaques of AD brains and show neurotoxicity for cultured nerve cells. We synthesized all variant forms of Abeta1-42 associated with reported FAD, such as A21G (Flemish), E22Q (Dutch), E22K (Italian), E22G (Arctic), and D23N (Iowa) along with three potential mutants by one point missense mutation (E22A, E22D, and E22V) in a highly pure form, and examined their ability to aggregate and their neurotoxicity in PC12 cells. The mutants at positions 22 and 23 showed potent aggregative ability and neurotoxicity whereas the potential mutants did not, indicating that Abeta1-42 mutants at positions 22 and 23 play a critical role in FAD of Dutch-, Italian-, Arctic-, and Iowa-types. However, Flemish-type FAD needs alternative explanation except the aggregation and neurotoxicity of the corresponding Abeta1-42 mutant. (C) 2002 Elsevier Science (USA). All rights reserved.