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* Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan;
Section of Cellular Physiological Chemistry, Tokyo Medical and Dental University, Tokyo, Japan; and
Laboratory for Proteolytic Neuroscience, Institute of Physical and Chemical Research (RIKEN) Brain Science Institute, Wako-shi, Saitama, Japan
The results of recent studies have implicated local inflammation and complement activation as the processes involved in the pathogenesis of age-related macular degeneration (AMD). We have demonstrated that amyloid β (Aβ), which is deposited in drusen, causes an imbalance in the angiogenesis-related factors in retinal pigment epithelial cells. We have also shown that neprilysin gene-disrupted mice accumulate Aβ, and develop several features of AMD. The purpose of this study was to investigate the mechanisms involved in the development of AMD that are triggered by Aβ. Our results showed that Aβ binds to complement factor I which inhibits the ability of factor I to cleave C3b to inactivated iC3b. Factor H and factor I are soluble complement-activation inhibitors, and preincubation of factor I with Aβ in the presence of factor H abolished the ability of Aβ to cleave C3b, and also abolished the ability of factor I to cleave FGR-AMC. In contrast, Aβ did not affect the function of factor H even after binding. The production of iC3b was significantly decreased when C3b and factor H were incubated with the eyes from neprilysin gene-disrupted mice as compared with when C3b and factor H were incubated with eyes from age-matched wild-type mice. These results suggest that Aβ activates the complement system within drusen by blocking the function of factor I leading to a low-grade, chronic inflammation in subretinal tissues. These findings link four factors that have been suggested to be associated with AMD: inflammation, complement activation, Aβ deposition, and drusen.
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1 This work was supported in part by Research Grants 19390441, 18023037, and 19659445 from the Japan Society for the Promotion of Science, Tokyo, Japan. This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas, Research on Pathomechanisms of Brain Disorders 18023037 (to N.I.) and 20023031 (to N.I.) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
2 Address correspondence and reprint requests to Dr. Kyoko Ohno-Matsui, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan. E-mail address: k.ohno.oph{at}tmd.ac.jp
3 Abbreviations used in this paper: MAC, membrane attack complex; AMD, age-related macular degeneration; RPE, retinal pigmented epithelium; Aβ, amyloid β; AD, Alzheimer’s disease; FGF, fibroblast growth factor; FHL, factor H-like protein.
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