A new amyloid μ variant favoring oligomerization in Alzheimer's-type dementia
A new amyloid μ variant favoring oligomerization in Alzheimer's-type dementia
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DOI：
10.1002/ana.21321
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发表时间：
2008-03-01
影响因子：
11.2
通讯作者：
Mori, Hiroshi
中科院分区：
文献类型：
--
作者：
Tomiyama, Takami;Nagata, Tetsu;Mori, Hiroshi
目的：淀粉样蛋白P（A β）的可溶性寡聚体，而不是淀粉样蛋白原纤维，已被提出在阿尔茨海默病（AD）中引发突触和认知功能障碍。然而，在人类中没有直接证据表明这种机制会导致AD。在这里，我们报告了一种新的淀粉样前体蛋白（APP）突变，可能提供证据来解决这个问题。方法：一个日本家系显示阿尔茨海默氏症型痴呆症进行了检查APP，PSEN 1和PSEN 2的突变。此外，5,310名日本人，包括2,121名AD患者，接受了新型APP突变筛查。这种突变对A β的产生，降解，聚集和突触毒性的致病作用也investigated.Results：我们确定了一种新的APP突变（E693三角洲）产生的变体A β缺乏gulutamate-22（E22 A）在日本家系显示阿尔茨海默氏症型痴呆症和AD。虽然总A β的分泌显着减少了这种突变，变体A β更耐蛋白水解降解。突变体肽显示出独特的聚集特性，增强寡聚化，但110 firidization，并抑制海马长时程增强比野生型肽在体内大鼠。与变体A β的非原纤维形成特性一致，在使用匹兹堡化合物B的正电子发射断层扫描中观察到非常低的淀粉样蛋白信号。解释：由于突触毒性A β寡聚体的形成增强，E693 Delta突变被认为是痴呆的原因。我们的研究结果可能为新出现的AD中突触和认知障碍主要由可溶性A β寡聚体引起的假说提供人类遗传学验证。
Objective: Soluble oligomers of amyloid P (A beta), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question.Methods: A Japanese pedigree showing Alzheimer's-type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on A beta production, degradation, aggregation, and synaptotoxicity were also investigated.Results: We identified a novel APP mutation (E693 Delta) producing variant A beta lacking gulutamate-22 (E22A) in Japanese pedigrees showing Alzheimer's-type dementia and AD. Although the secretion of total A beta was markedly reduced by this mutation, the variant A beta was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but 110 fibrillization, and inhibited hippocampal long-term potentiation more potently than wild-type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant A beta, a very low amyloid, signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound-B.Interpretation: The E693 Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic A beta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble A beta oligomers.