Abstract Th0030: Impact of Atherosclerosis-Induced Cellular Senescence on Vascular Cognitive Impairment and Dementia

Vascular Cognitive Impairment Disease (VCID) ranks as the second most prevalent form of dementia, after Alzheimer's disease, and is closely linked to cardiovascular diseases (CVDs). Recent research has identified the abnormal accumulation of senescent cells as a novel mechanism linking cellular senescence with atherosclerosis. Conditions such as hypertension, heart disease, and specifically atherosclerosis are major risk factors for VCID. Atherosclerosis induces cellular senescence within the aorta, characterized by heightened senescence-associated beta-galactosidase in vascular smooth muscle cells, endothelial cells, and immune cells. Given that atherosclerosis affects the body's largest artery and can broadly impact organs, including the brain, we hypothesize that atherosclerosis may induce senescence via remote plaque formation or activation of the senescence-associated secretory phenotype (SASP). To examine this hypothesis, we utilized mice susceptible to developing atherosclerosis when fed a high-fat diet (HFD). A subset of HFD mice then received ABT-737, a senolytic drug that selectively kills senescent cells. Pulse wave velocity measurements revealed a significant increase in arterial stiffness in HFD mice, while ABT-737 treatment led to a substantial reduction in stiffness. Interestingly, in male atherosclerotic mice, we observed an increase in anxiety, although senolytic ABT-737 did not appear to rescue this effect. Surprisingly, ABT-737 alone improved spatial long-term memory, independent of disease. In a measure of locomotor activity, atherosclerosis significantly reduced nocturnal activity levels which were subsequently increased by ABT-737. Using mass spectrometry on brain tissue, we found that a subset of differentially expressed proteins have an inverse relationship in HFD compared to HFD + ABT-737. Proteins involved with cholesterol transport and cell signaling were significantly increased in HFD; while proteins involved in the initiation of translation were significantly decreased. When compared to HFD + ABT-737 mice, significantly expressed proteins in both directions returned to baseline. Our findings suggest that disease-driven (atherosclerosis) secondary senescence promotes VCID, impairing specific areas of brain function (amygdala and hippocampus) which is potentially mediated by immune cell recruitment, translation, and cholesterol homeostasis.