Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.
Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease.
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DOI：
10.1007/s00401-018-1866-3
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发表时间：
2018-10
影响因子：
12.7
通讯作者：
Strydom A
中科院分区：
文献类型：
--
作者：
Mann DMA;Davidson YS;Robinson AC;Allen N;Hashimoto T;Richardson A;Jones M;Snowden JS;Pendleton N;Potier MC;Laquerrière A;Prasher V;Iwatsubo T;Strydom A
在这项研究中，我们比较了AD的APP遗传原因(APP基因突变)、表现为阿尔茨海默病(AD)病理的唐氏综合征(DS)和散发性(早发和晚发)AD患者(分别为sEOAD和sLOAD)之间淀粉样斑块形成和脑淀粉样血管病变(CAA)的严重程度以及CAA病理本身的亚型模式。这样做的目的是阐明重要的群体差异，并提供与临床和神经病理表型相关的机械性见解。由于脂质和胆固醇代谢与AD和血管疾病有关，我们还旨在探讨APOE基因在CAA严重程度和亚型中的作用。DS和错义APP突变的斑块形成比APPdup、sEOAD和sLOAD病例更大。相反，与sEOAD和sLOAD相比，APPdup和错义APP突变以及DS患者的CAA更为严重。当按CAA亚型从1到4分层时，两组间斑块评分没有差异，但在APPdup、APP突变和sEOAD患者中，2型和3型CAA比1型更常见。相反，在DS、sLOAD和对照组中，1型CAA比2型和3型更常见。与APPdup、APP错义突变、DS和对照组相比，sEOAD和sLOAD中APOEε4等位基因频率更高，且APOEε4纯合子与3A型CAA的相关性在sLOAD和sEOAD中各不相同。每组个体CAA的不同模式可能反映了血管周围引流效率的差异，这在2型和3型CAA中效果较差，导致实质动脉和毛细血管的CAA负担较大。或者，正如使用羧基末端特异性抗体进行免疫染色所表明的那样，这可能与两种主要形式的Aβ的相对组织负担有关，较高水平的Aβ40促进更具侵袭性的形式的CAA，而较高水平的Aβ42(3)有利于更大的斑块负担。ApoEε4等位基因，尤其是ε4纯合子，总体上有利于慢性再生障碍性贫血的发生，尤其是3型，在sEOAD和sLOAD中更为明显。本文的在线版本(10.1007/s00401181866-3)包含向授权用户提供的补充材料。
In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, between APP genetic causes of AD (APPdup, APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer’s disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vascular disease, we additionally aimed to explore the role of APOE genotype in CAA severity and subtypes. Plaque formation was greater in DS and missense APP mutations than in APPdup, sEOAD and sLOAD cases. Conversely, CAA was more severe in APPdup and missense APP mutations, and in DS, compared to sEOAD and sLOAD. When stratified by CAA subtype from 1 to 4, there were no differences in plaque scores between the groups, though in patients with APPdup, APP mutations and sEOAD, types 2 and 3 CAA were more common than type 1. Conversely, in DS, sLOAD and controls, type 1 CAA was more common than types 2 and 3. APOE ε4 allele frequency was greater in sEOAD and sLOAD compared to APPdup, missense APP mutations, DS and controls, and varied between each of the CAA phenotypes with APOE ε4 homozygosity being more commonly associated with type 3 CAA than types 1 and 2 CAA in sLOAD and sEOAD. The differing patterns in CAA within individuals of each group could be a reflection of variations in the efficiency of perivascular drainage, this being less effective in types 2 and 3 CAA leading to a greater burden of CAA in parenchymal arteries and capillaries. Alternatively, as suggested by immunostaining using carboxy-terminal specific antibodies, it may relate to the relative tissue burdens of the two major forms of Aβ, with higher levels of Aβ40 promoting a more ‘aggressive’ form of CAA, and higher levels of Aβ42(3) favouring a greater plaque burden. Possession of APOE ε4 allele, especially ε4 homozygosity, favours development of CAA generally, and as type 3 particularly, in sEOAD and sLOAD. The online version of this article (10.1007/s00401-018-1866-3) contains supplementary material, which is available to authorized users.
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影响因子：
7.1
作者：
Davidson YS;Barker H;Robinson AC;Thompson JC;Harris J;Troakes C;Smith B;Al-Saraj S;Shaw C;Rollinson S;Masuda-Suzukake M;Hasegawa M;Pickering-Brown S;Snowden JS;Mann DM
通讯作者：
Mann DM
影响因子：
7.1
作者：
Head E;Phelan MJ;Doran E;Kim RC;Poon WW;Schmitt FA;Lott IT
通讯作者：
Lott IT
影响因子：
11.2
作者：
Gearing, M;Mori, H;Mirra, SS
通讯作者：
Mirra, SS
影响因子：
4.2
作者：
Lott, IT;Head, E
通讯作者：
Head, E
影响因子：
5.2
作者：
Blom, Elin S.;Viswanathan, Jayashree;Hiltunen, Mikko
通讯作者：
Hiltunen, Mikko