ABT263 Ameliorates Cellular Senescence, Aβ-Dependent Pathology and Cognitive Decline in Aged APP/PS1 Mice via...

Alzheimer's disease is defined pathologically by the irregular buildup of senile plaques, neurofibrillary tangles, and associated neuroinflammation. As aging progresses, senescent cells gradually accumulate and significantly contribute to brain dysfunction; however, the precise mechanisms driving aging remain unclear. In the current study, ABT263, a potent senolytic drug, was administered orally to APP/PS1 mice (n = 16) for five days per cycle throughout the course of two cycles, and their behavioral tests in the Morris water maze were evaluated. Using mouse hippocampal tissue, senescence-related gene expression and SASP-associated protein expression were assessed using biochemical tests and immunohistochemical labeling. The Morris water maze test results indicated that ABT263 alleviated spatial memory impairment and reduced amyloid-β (Aβ) accumulation in APP/PS1 mice. Additionally, ABT263 treatment led to a decline in senescence-associated β-galactosidase activity, p16 senescence-related gene expression, and the expression of SASP-associated proteins, including IL-6, IL-8, and MMP-1. Further investigation revealed that ABT263 enhanced the phosphorylation levels of phosphatidylinositol-3 kinase (PI3K) (Tyr458), serine/threonine kinase AKT (S473), and glycogen synthase kinase-3β (GSK-3β) (Ser9) in APP/PS1 mice. Our results showed that ABT263 protected neurons against Aβ pathology, reduced the accumulation of senescent cells, and improved cognitive decline by enhancing PI3K/AKT/GSK-3 activity.