Abstract
<title>Abstract</title> <p> This research sought to assess the prophylactic effects of corilagin (CORG), an ellagitannin, on D-galactose (D-gal) neurodegeneration associated with aging and to elucidate the underlying mechanisms. The anti-neuroinflammatory effects of CORG were investigated <italic>in vitro</italic> using D-gal-treated cultured microglial BV-2 cells and a co-culture system of BV-2 cells and primary cortical neurons. CORG effectively B ehanced the V-ATPase activity, decreased lysosomal pH, and led to lysosomal Ca <sup>2+</sup> release and inhibited the levels of inflammatory cytokines triggered by D-gal in BV-2 cells. Furthermore, CORG protected primary neuronal cells from synaptic damage resulting from neuroinflammation mediated by BV-2 microglia. The <italic>in vitro</italic> findings indicated that CORG enhanced cognitive abilities and behavioral issues, decreased hippocampal damage, and synaptic plasticity dysfunction, modulatd the expression of inflammatory proteins and eased aging symptoms. CORG further inhibited microglial overactivation by activating the V-ATPase-AMPK signaling pathway in both aging mouse brains and cultured BV-2 cells. Further results from V-ATPase B2/TRPML1/Ca <sup>2+</sup> /CaMKK2/ AMPK inhibition experiments revealed that inhibition of V-ATPase B2, TRPML1, Ca <sup>2+</sup> , CaMKK2, AMPK all could abolish the protective effects of CORG. The validation experiments of the target showed that the interaction between V-ATPase B2 and CORG maintained a stable conformation, leading to the speculation that V-ATPase B2 is the primary target of V-ATPase B2. In summary, CORG alleviated cognitive deficits and behavioral disorders in aging mice <italic>via</italic> amelioration of neuroinflammation through activation of the V-ATPase-AMPK axis to modulate metabolic remodeling. These findings indicate that CORG could be a potential treatment for aging and neurodegenerative diseases associated with aging. </p>