Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis
Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis
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DOI：
10.1038/nn1302
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发表时间：
2004-09-01
影响因子：
25
通讯作者：
Jucker, M
中科院分区：
文献类型：
--
作者：
Herzig, MC;Winkler, DT;Jucker, M
淀粉样β前体蛋白(APP)中的E693Q突变会导致脑淀粉样血管病(CAA)，并伴有反复出血性中风和痴呆。与阿尔茨海默病(AD)相比，遗传性脑出血伴淀粉样变性-荷兰型(HCHWA-D)患者的大脑显示出很少的实质淀粉样斑块。我们发现，人E693Q APP在小鼠(APPDutch小鼠)中的神经元过表达导致广泛的CAA、平滑肌细胞变性、出血和神经炎症。相反，人类野生型APP(APPwt小鼠)的过度表达导致了主要的实质性淀粉样变性，类似于AD。在APPDutch小鼠和HCHWA-D人脑中，淀粉样β40肽(Abeta40)和Abeta42的比率显著高于APPwt小鼠或AD人脑。通过将APPDutch小鼠与产生突变的早老素-1的转基因小鼠杂交，将Abetaduch40/AbetaHolch42的比例基因转移到AbetaHolch42，将淀粉样蛋白的病理从血管系统重新分布到实质。了解不同的Abeta物种可以在不同的脑区导致淀粉样蛋白病理，这一理解对目前的抗淀粉样蛋白治疗策略具有重要意义。这个HCHWA-D小鼠模型是第一个在没有实质淀粉样蛋白的情况下发展出强大的CAA的模型，强调了神经元产生的Abeta在血管淀粉样蛋白病理中的关键作用，并强调了Abeta40和Abeta42在血管和实质淀粉样蛋白病理中的不同作用。
The E693Q mutation in the amyloid beta precursor protein (APP) leads to cerebral amyloid angiopathy (CAA), with recurrent cerebral hemorrhagic strokes and dementia. In contrast to Alzheimer disease ( AD), the brains of those affected by hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) show few parenchymal amyloid plaques. We found that neuronal overexpression of human E693Q APP in mice (APPDutch mice) caused extensive CAA, smooth muscle cell degeneration, hemorrhages and neuroinflammation. In contrast, overexpression of human wild-type APP (APPwt mice) resulted in predominantly parenchymal amyloidosis, similar to that seen in AD. In APPDutch mice and HCHWA-D human brain, the ratio of the amyloid-beta40 peptide (Abeta40) to Abeta42 was significantly higher than that seen in APPwt mice or AD human brain. Genetically shifting the AbetaDutch40/AbetaDutch42 ratio toward AbetaDutch42 by crossing APPDutch mice with transgenic mice producing mutated presenilin-1 redistributed the amyloid pathology from the vasculature to the parenchyma. The understanding that different Abeta species can drive amyloid pathology in different cerebral compartments has implications for current anti-amyloid therapeutic strategies. This HCHWA-D mouse model is the first to develop robust CAA in the absence of parenchymal amyloid, highlighting the key role of neuronally produced Abeta to vascular amyloid pathology and emphasizing the differing roles of Abeta40 and Abeta42 in vascular and parenchymal amyloid pathology.