文章基本信息

标题：Amyloid β peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice
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作者：Tuhina Prasad ; Ping Zhu ; Amrisha Verma 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2017
卷号：7
期号：1
DOI：10.1038/s41598-017-03397-2
语种：English
出版社：Springer Nature
摘要：Age-related macular degeneration (AMD) is a progressive retinal neurodegenerative disorder characterized by extracellular deposits known as drusen. A major constituent of drusen deposits are Alzheimer disease-associated amyloid β (Aβ) peptides. To understand the etiology of Aβ proteostasis in AMD, we delivered recombinant adeno-associated virus (AAV) encoding Aβ42 and Aβ40 peptides fused to BRI2 protein by intraocular injection in C57BL/6J mice. Endogenous protease cleavage of such constructs leads to production of secreted Aβ42 and Aβ40 respectively. We demonstrate that overexpression of secreted Aβ40 or Aβ42 resulted in dramatic induction of drusen-like deposits by 2 months' post-injection. These drusen-like deposits were immunopositive for Aβ and complement proteins but did not stain for conventional amyloid dyes, such as Thioflavin S. Both injected cohorts showed gliosis and degenerative changes, though ERG responses were minimally affected. Intriguingly, simultaneous overexpression of BRI-Aβ40 or BRI-Aβ42 together resulted in dose-dependent and cumulative changes reminiscent of AMD type pathology - drusen-like deposits, severe reduction in ERG responses, photoreceptor cell loss and gliosis. Here, we have established a physiological model of Aβ containing deposits in wild-type mice that recapitulates major retinal pathophysiological features of AMD and will be instrumental in mechanistic understanding and development of therapeutic strategies against AMD.