Targeting angiopoietin like-2 positive senescent cells improves cognitive impairment in adult male but not female atherosclerotic LDLr−/−;hApoB100+/+ mice

Cellular senescence contributes to cognitive decline in brain diseases. In dyslipidemic and atherosclerotic LDLr^-/-;hApoB100^+/+ (ATX) mice-a model exhibiting vascular dysfunctions and cognitive impairment-the role of senescence was investigated by targeting angiopoietin-like 2 (angptl2), a senescence marker. Adult ATX mice of both sexes received AAV1-sh-angptl2; cognition was assessed via the Morris Water Maze, cerebrovascular functions were evaluated in vitro and in vivo and hippocampal transcriptomic signatures were analyzed using single-nuclei RNA-sequencing. Sh-angptl2 restored delayed memory retention in male mice, but impaired learning and short-term memory in females. Sh-angptl2 had no effect on cerebrovascular functions. Transcriptomic analyses revealed sex-specific responses: endothelial senescence pathways were predominantly activated in male cells and repressed by sh-angptl2. In contrast, sh-angptl2 up-regulated senescence pathways in all cell types in females. Key impacted senescent cell types were neurons, choroid plexus epithelial (CP-epithelial) cells, and oligodendrocyte precursor cells (OPCs), not endothelial cells. In male neurons, CP-epithelial cells and OPCs, gene-related pathways induced by sh-angptl2 revealed enhanced neuronal energy metabolism but reduced synaptic pathways, higher synaptic formation with reduced intracellular signaling, structural remodeling and reduced synaptic development. In female cells, sh-angptl2 disrupted GABAergic signaling despite promoting neuronal growth, up-regulated stress-response and decreased gene and protein processing, leading to inefficient neurogenesis. Although neuroprotective ApoE was upregulated in both sexes, males had higher expression of ApoE receptor subtypes, supporting better synaptic resilience. In conclusion, accumulation of non-vascular senescent cells contributes to cognitive impairment in male ATX mice, not females, highlighting the need for sex-specific senotherapies strategies in cardiovascular diseases.