CD2AP impacts Alzheimer’s disease through brain vascular function
Milene Vandal, Adam Institoris, Ben Korin, Colin Gunn, Suzie Lee, Jiyeon Lee, Philippe Bourassa, Ramesh C Mishra, Govind Peringod, Yulan Jiang, Sotaro Hirai, Camille Belzil, Louise Reveret, Cyntia Tremblay, Mada Hashem, Esteban Elias, William Meilandt, Oded Foreman, Meron Rouse‐Girma, Daniel Muruve, Wilten Nicola, Jakob Körbelin, Jeff F Dunn, Andy P. Braun, David A. A Bennett, Grant Gordon, Frederic Calon, Andrey S Shaw, Minh Dang Nguyen- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Cerebrovascular impairment is a key aspect of Alzheimer’s Disease (AD) pathogenesis. Brain vascular defects appear early in the disease process and are associated with cognitive dysfunction. CD2‐associated protein (CD2AP), a scaffolding protein involved cytoskeleton remodeling and membrane trafficking, is an important predisposing factor for the disease. The protein is enriched in brain endothelial cells (BECs) that forms the brain vessels, suggesting that CD2AP might contribute to AD cerebrovascular dysfunction.
Method
In this study, we used brain samples from AD volunteers, genetically modified mouse models, awake two‐photon microscopy and cell culture to investigate the function of CD2AP in the brain vasculature.
Result
We found that AD individuals with lower levels of brain vascular CD2AP displayed the poorest cognitive performance. Genetic depletion of CD2AP in BECs compromised memory function, cerebral blood flow and increased vessels vulnerability to amyloid‐beta. In BECs, CD2AP controlled the levels and signaling of Apolipoprotein E Receptor 2 (ApoER2) and activation of this pathway with Reelin glycoprotein in mice depleted of endothelial CD2AP mitigated the toxic effects of peptide.
Conclusion
In sum, deregulation of endothelial CD2AP drives cerebrovascular dysfunction, and harnessing the biology of specific brain vessel types may offer a refined therapeutic avenue for the treatment of AD.