Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer's disease and transgenic mouse models.
Deposition of C-terminally truncated Aβ species Aβ37 and Aβ39 in Alzheimer's disease and transgenic mouse models.
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DOI：
10.1186/s40478-016-0294-7
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发表时间：
2016-03-08
影响因子：
7.1
通讯作者：
Wirths O
中科院分区：
文献类型：
--
作者：
Reinert J;Richard BC;Klafki HW;Friedrich B;Bayer TA;Wiltfang J;Kovacs GG;Ingelsson M;Lannfelt L;Paetau A;Bergquist J;Wirths O
在阿尔茨海默病(AD)中，各种淀粉样多肽(Aβ-β)以细胞外弥漫性和神经性斑块(NP)的形式沉积在血管系统内。从其前体淀粉样前体蛋白(APP)生成Aβ是一个高度复杂的过程，涉及β-和γ-分泌酶随后对APP的蛋白分解。由于Aβ降解受损和/或产生的不同Aβ物种之间的比率改变而导致的Aβ脑积聚被认为在AD的发病机制中起着关键作用。虽然Aβ40和Aβ42在血管和实质淀粉样蛋白中的存在已被广泛研究，但在AD中羧基末端截短的Aβ多肽的沉积还没有得到类似的关注。在本研究中，我们首次证明了Aβ37和Aβ39在人类散发性AD中的免疫组织化学定位。我们的研究还包括对携带APP突变KM670/671NL、E693G和I716F的家族性AD(FAD)病例以及1例PSEN1Δ外显子9突变的病例进行了分析。研究发现Aβ37和Aβ39广泛分布于大多数SAD和FAD患者的脑血管内，后者也存在相当数量的含有NPs的Aβ37。此外，这两种多肽都被发现存在于细胞外斑块中，但只有在各种转基因AD小鼠模型的脑血管内才稀少。综上所述，我们的研究表明了C末端截短的Aβ在散发性和家族性AD中的重要性，并提出了关于这些物种是如何产生和调节的问题。本文的在线版本(doi：10.1186/s40478-0160294-7)包含补充材料，授权用户可以使用。
In Alzheimer’s disease (AD) a variety of amyloid β-peptides (Aβ) are deposited in the form of extracellular diffuse and neuritic plaques (NP), as well as within the vasculature. The generation of Aβ from its precursor, the amyloid precursor protein (APP), is a highly complex procedure that involves subsequent proteolysis of APP by β- and γ-secretases. Brain accumulation of Aβ due to impaired Aβ degradation and/or altered ratios between the different Aβ species produced is believed to play a pivotal role in AD pathogenesis. While the presence of Aβ40 and Aβ42 in vascular and parenchymal amyloid have been subject of extensive studies, the deposition of carboxyterminal truncated Aβ peptides in AD has not received comparable attention. In the current study, we for the first time demonstrate the immunohistochemical localization of Aβ37 and Aβ39 in human sporadic AD (SAD). Our study further included the analysis of familial AD (FAD) cases carrying the APP mutations KM670/671NL, E693G and I716F, as well as a case of the PSEN1 ΔExon9 mutation. Aβ37 and Aβ39 were found to be widely distributed within the vasculature in the brains of the majority of studied SAD and FAD cases, the latter also presenting considerable amounts of Aβ37 containing NPs. In addition, both peptides were found to be present in extracellular plaques but only scarce within the vasculature in brains of a variety of transgenic AD mouse models. Taken together, our study indicates the importance of C-terminally truncated Aβ in sporadic and familial AD and raises questions about how these species are generated and regulated. The online version of this article (doi:10.1186/s40478-016-0294-7) contains supplementary material, which is available to authorized users.