Vandal Milene1, Gunn Colin1*, Bourassa Philippe2,3*, Seungjae Shin Steven4, Belzil Camille1, Jiang Yulan1, Tremblay Cyntia3, Bennett David5, Gordon Grant4, Calon Frédéric2,3, Minh Dang Nguyen1 *These authors contribute equally to this work 1Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada; 2Faculté de pharmacie, Université Laval, Québec, Québec, Canada; 3Axe Neurosciences, Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; 4Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; 5Rush Alzheimer's disease Center, Rush University Medical Center, 600 S. Paulina Street, Chicago, IL 60612, United States
Alzheimer Disease (AD) is the most prevalent form of dementia in the elderly. Although the causes of the disease remain elusive, several risk factors have been identified. Interestingly, many of these factors are associated with blood brain barrier abnormalities. Indeed, apolipoprotein E4 genotype, type 2 diabetes and hypertension are all linked to defects in the cerebrovasculature. CD2AP, a scaffolding protein implicated in receptor recycling and cell-cell interaction was identified as one of the top 10 genetic predisposition factors for AD. Human studies have shown that CD2AP is linked to the plaque burden and cognitive function. However, the role of the protein in AD pathogenesis remains unclear. In this study, we show that CD2AP levels are altered in AD brains from the Religious Order Study, correlating with amyloid plaques. We also found that the CD2AP protein is highly enriched in brain capillary endothelial cells that form brain microvessels in human and mouse. In cultured mouse primary and human brain capillary endothelial cells, we observed that CD2AP is involved receptor recycling. We propose that alterations in CD2AP contribute to brain vascular dysfunction via abnormal receptor recycling, thereby increasing the risk for AD.
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