Impact of atherosclerosis-induced cellular senescence on vascular cognitive impairment and dementia (VCID) (Alzheimers disease)

National Institute On Aging

Investigators

Abstract

VCID is one of the most common forms of age-related dementias, yet, considering its prevalence, it has been understudied and lacks strong mechanistic understanding. Atherosclerosis is an age-related vascular disease that has been associated with increased likelihood of cognitive decline, but the link between the two is not well defined. Studies have shown an increased abundance of senescent cells in both human and mouse atherosclerotic plaques and arteries. Preliminary data from our lab has identified increased senescence markers and inflammatory cytokines in the brains of atherosclerotic mice. Further, immunofluorescent staining demonstrated increased p16 and Td Tomato co-localization and expression in the hippocampus and cortex of atherosclerotic mice compared to control mice. We seek to determine if atherosclerosis is a source of senescent cells in the brain that cause structural and behavioral changes associated with VCID. To do so, we will use the Proprotein convertase subtilisin/kexin type 9 (PCSK9) mutant overexpressing virus to downregulate the low-density lipoprotein receptor to promote atherosclerosis with high-fat feeding (Objective 1). Simultaneously, we will determine if aging along with atherosclerosis increases the presence of senescent cells, structural changes, and behavioral declines associated with VCID (Objective 2). Finally, we will determine if treating young and old atherosclerotic mice with senolytic drugs reduces the abundance of senescent cells in the brain, improves or preserves brain architecture, and prevents behavioral declines associated with loss of cognition during VCID (Objective 3). Several of these studies will serve as the basis for further investigation to be continued beyond this funding period.