Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice.
Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice.
复制标题
早发性实质斑块淀粉样蛋白的形成消除了转基因小鼠脑微血管淀粉样蛋白的积累。
DOI：
10.1074/jbc.m113.536565
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
VanNostrand,WilliamE
中科院分区：
文献类型：
--
作者：
Xu,Feng;Kotarba,AnnMarieE;Ou-Yang,Ming-Hsuan;Fu,Ziao;Davis,Judianne;Smith,StevenO;VanNostrand,WilliamE
The fibrillar assembly and deposition of amyloid β (Aβ) protein, a key pathology of Alzheimer disease, can occur in the form of parenchymal amyloid plaques and cerebral amyloid angiopathy (CAA). Familial forms of CAA exist in the absence of appreciable parenchymal amyloid pathology. The molecular interplay between parenchymal amyloid plaques and CAA is unclear. Here we investigated how early-onset parenchymal amyloid plaques impact the development of microvascular amyloid in transgenic mice. Tg-5xFAD mice, which produce non-mutated human Aβ and develop early-onset parenchymal amyloid plaques, were bred to Tg-SwDI mice, which produce familial CAA mutant human Aβ and develop cerebral microvascular amyloid. The bigenic mice presented with an elevated accumulation of Aβ and fibrillar amyloid in the brain compared with either single transgenic line. Tg-SwDI/Tg-5xFAD mice were devoid of microvascular amyloid, the prominent pathology of Tg-SwDI mice, but exhibited larger parenchymal amyloid plaques compared with Tg-5xFAD mice. The larger parenchymal amyloid deposits were associated with a higher loss of cortical neurons and elevated activated microglia in the bigenic Tg-SwDI/Tg-5xFAD mice. The periphery of parenchymal amyloid plaques was largely composed of CAA mutant Aβ. Non-mutated Aβ fibril seeds promoted CAA mutant Aβ fibril formationin vitro. Further, intrahippocampal administration of biotin-labeled CAA mutant Aβ peptide accumulated on and adjacent to pre-existing parenchymal amyloid plaques in Tg-5xFAD mice. These findings indicate that early-onset parenchymal amyloid plaques can serve as a scaffold to capture CAA mutant Aβ peptides and prevent their accumulation in cerebral microvessels.
