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 tdTomato co-localization and expression in the hippocampus and cortex of atherosclerotic mice compared to control mice. We performed a series of functional and behavior tests on control, atherosclerotic mice fed a high-fat diet (HFD), and atherosclerotic mice treated with a senolytic drug, ABT-737. The preliminary results suggest male HFD mice had reduced homecage locomotor activity during their dark (wake) phase, showed increased anxiety-like behavior in both the open field test and elevated plus maze, and displayed impairment in long-term spatial memory and that this effect was potentially rescued by ABT-737. Pulse wave velocity data revealed increased arterial stiffening in HFD mice compared to control mice and that treatment with ABT-737 rescued this phenotype. Together, these data suggest that atherosclerotic male mice exhibit cognitive decline that may be rescued by senolytic drug, ABT-737.