Astrocytic Hevin/<scp>SPARCL</scp>‐1 Regulates Cognitive Decline in Pathological and Normal Brain Aging

Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of Aβ plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression. In conclusion, our results propose astrocytic Hevin as a potential therapeutic target for age-associated cognitive decline.