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

Authors

• X Wu
• A Gruzdev
• JG Williams
• I Shats
• X L

Abstract

Vascular Cognitive Impairment Disease (VCID) is an increasingly prevalent form of dementia that is second only to Alzheimer’s disease in incidence. Many risk factors for VCID include cardiovascular diseases (CVD) such as atherosclerosis and hypertension, suggesting a strong link between VCID and CVD. Given the presence of vascular smooth muscle cells, endothelial cells, and immune cells displaying senescent-like phenotypes, i.e., increased activity of SA-βGal (senescence-associated β-galactosidase), in atherosclerotic lesions, it has been reported that atherosclerosis can cause cellular senescence within the aorta. Because atherosclerosis is a disease of the largest artery and can impact all organs and tissues, we hypothesize that atherosclerosis can promote senescence in other organs, such as the brain, either by plaque formation in remote locations or by triggering the senescence associated secretory phenotype (SASP). To test our hypothesis, 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.

Scientific Focus Area: ACI/IRS

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