Presence of soluble amyloid β–peptide precedes amyloid plaque formation in Down's syndrome
Presence of soluble amyloid β–peptide precedes amyloid plaque formation in Down's syndrome
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唐氏综合症中可溶性淀粉样β肽的存在先于淀粉样蛋白斑块的形成
DOI：
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
P. Gambetti
中科院分区：
文献类型：
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作者：
J. Teller;C. Russo;L. Debusk;G. Angelini;D. Zaccheo;F. Dagna;P. Scartezzini;S. Bertolini;D. Mann;M. Tabaton;P. Gambetti
淀粉样蛋白β多肽(Aβ)在大脑中异常和过度积聚是所有阿尔茨海默病(AD)形式的主要和共同特征，无论其遗传背景如何。Aβ的不溶性聚集体被鉴定为淀粉样斑块。这些沉积物被认为是由于淀粉样前体蛋白(APP)1-3的过度表达或改变处理而导致脑实质中Aβ含量增加时形成的。在细胞培养中，终止于羧基末端残基40的可溶性Aβ(Aβ40)和少量终止于残基42的形式(Aβ42)是APP代谢的正常产物。在构建了家族性AD APP基因突变模型的细胞中，观察到可溶性Aβ42的分泌增加(参考文献4，5)。根据这些体外数据推测，可溶性Aβ42的存在在淀粉样斑块的形成中起作用。患有唐氏综合症(DS)的受试者APP基因剂量增加，APP过度表达。显然，由于这种过度表达，他们几乎总是在30岁后形成淀粉样沉积，尽管他们在较早的6，7岁时没有淀粉样沉积。此外，已经观察到，在DS脑8中，Aβ42先于Aβ40沉积。因此，DS受试者提供了在人脑中研究淀粉样蛋白沉积形成之前的代谢条件的机会。在这里，我们报告了在21周至61岁的DS患者的大脑中存在可溶性Aβ42，但在年龄匹配的对照组中检测不到它。有人认为，APP的过度表达特异性地导致Aβ42的增加，并且可溶性Aβ42的存在与DS和AD脑中斑块的形成有因果关系。
Abnormal and excessive accumulation of the amyloid β–peptide (Aβ) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of Aβ are identified as amyloid plaques. These deposits are thought to form when the amount of Aβ is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP)1–3. Soluble Aβ ending at carboxyl–terminal residue 40 (Aβ40) and, in lesser amount, the form ending at residue 42 (Aβ42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble Aβ42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble Aβ42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages6,7. Moreover, it has been observed that Aβ42 precedes Aβ40 in the course of amyloid deposition in DS brain8. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble Aβ42 is present in the brains of DS–affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age–matched controls. It is argued that overexpression of APP leads specifically to Aβ42 increase and that the presence of the soluble Aβ42 is causally related to plaque formation in DS and, likely, in AD brains.
影响因子：
56.9
作者：
SUZUKI, N;CHEUNG, TT;YOUNKIN, SG
通讯作者：
YOUNKIN, SG
影响因子：
56.9
作者：
CAI, XD;GOLDE, TE;YOUNKIN, SG
通讯作者：
YOUNKIN, SG