Comparative benefits of simvastatin and exercise in a mouse model of vascular cognitive impairment and dementia

Aerobic physical exercise (EX) and controlling cardiovascular risk factors in midlife can improve and protect cognitive function in healthy individuals and are considered to be effective at reducing late‐onset dementia incidence. By investigating commonalities between these preventative approaches, we sought to identify possible targets for effective interventions. We compared the efficacy of EX and simvastatin (SV) pharmacotherapy to counteract cognitive deficits induced by a high‐cholesterol diet (2%, HCD) in mice overexpressing TGF‐β1 (TGF mice), a model of vascular cognitive impairment and dementia. Cognitive deficits were found in hypercholesterolemic mice for object recognition memory, and both SV and EX prevented this decline. EX improved stimulus‐evoked cerebral blood flow responses and was as effective as SV in normalizing endothelium‐dependent vasodilatory responses in cerebral arteries. The up‐regulation of galectin‐3‐positive microglial cells in white matter (WM) of HCD‐fed TGF mice with cognitive deficits was significantly reduced by both SV and EX concurrently with cognitive recovery. Altered hippocampal neurogenesis, gray matter astrogliosis, or microgliosis did not correlate with cognitive deficits or benefits. Overall, results indicate that SV and EX prevented cognitive decline in hypercholesterolemic mice and that they share common sites of action in preventing endothelial cell dysfunction and reducing WM inflammation.