disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human apoe ε4 allele混乱的大脑动脉血管周的排水的amyloid-β老鼠表达人类apoeε4等位基因.pdfVIP

Disruption of Arterial Perivascular Drainage of Amyloid- b from the Brains of Mice Expressing the Human APOE e4 Allele 1 2 3 1 1 Cheryl A. Hawkes , Patrick M. Sullivan , Sarah Hands , Roy O. Weller , James A.R. Nicoll , Roxana O. Carare1* 1 Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom, 2 Department of Medicine, Duke University, Durham VA Medical Center and GRECC, Durham, North Carolina, United States of America, 3 Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, United Kingdom Abstract Failure of elimination of amyloid-b (Ab) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) e4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE e4 allele is associated with disruption of perivascular drainage of Ab from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Ab40. Ab40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Ab deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Ab was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrate