The Effect of Accumulation of Cerebrovascular Senescent Endothelial Cells in Vascular Cognitive Impairment and Dementia

Cognitive functions decline with aging and a vascular contribution to neuronal damage has been proposed. Accumulation of senescent cells (SnC) is associated with age. SnC remain metabolically active and release numerous factors of Senescence-Associated Secretory Phenotype potentially harmful. Our hypothesis is that accumulation of cerebrovascular senescent endothelial cells (SnEC) contributes to vascular cognitive impairment and dementia (VCID). We pose that elimination of SnEC maintains cerebrovascular homeostasis and prevents cognitive dysfunction. To test our hypothesis we will eliminate SnEC by targeting angiopoietin-like 2 (angptl2), a new target in SnEC that leads to their death by apoptosis upon inactivation. A shRNA targeting angptl2 will be delivered to endothelial cells using AAV1 in a mouse model of VCID, severely dyslipidemic/atherosclerotic. Cognition will be assessed three months post injection, cerebral blood flow measured by 7T-MRI, followed by brain immunohistochemistry and molecular determination of SnC load. This novel therapeutic concept called senolysis is emerging and promising.

Faculty Supervisor:

Eric Thorin

Student:

Partner:

Universidade Federal de Minas Gerais

Discipline:

Life Sciences

Sector:

Education

University:

Université de Montréal

Program: