The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr−/−;hApoB100+/+ mice

Abstract

Accumulation of cerebral senescent cells may compromise the continuum between vascular and neuronal function, leading to damage and cognitive decline. Elimination of senescent cells might therefore preserve vascular and neuronal functions. To test this hypothesis, we used male and female atherosclerotic LDLr^−/−;hApoB₁₀₀^+/+ mice (ATX-mice), a model of vascular cognitive impairment (VCI), treated with the senolytic ABT-263 for 3 months (3- to 6-month or 9- to 12-month old). In young male ATX mice, prevention with ABT-263 improved spatial retention memory, in association with a higher endothelial sensitivity to shear stress and a higher hippocampal CD31⁺ endothelial cell density, lower activation of both astrocytes and glial cells. In young females, ABT-263 tended to improve delayed memory; however, atherosclerotic plaque was magnified by ABT-263, endothelial function was unaffected, hippocampal astrocyte activation increased and expression of CD31⁺ cells decreased. Hence, unlike in males, ABT-263 appears deleterious in young ATX females. In middle-aged males, the curative treatment improved the learning process and memory. Although no change in endothelial function was observed, the benefits of ABT-263 were associated with a decreased expression of several inflammaging markers, a higher density of CD31⁺ cells and a lower activation of glial cells. In middle-aged females, ABT-263 induced a surge of inflammaging markers, associated with a slower learning process. Altogether, our data demonstrate that ABT-263 differentially affects VCI, improving cognition in male while being deleterious in female ATX mice. More studies are needed to understand the mechanisms at the basis of the sexual dimorphic effects of the senolytic ABT-263.