Tinosinenside A ameliorates Alzheimer's disease-related pathology in APP/PS1 mice, accompanied by reduced neuroinflammation and altered microglial phenotype-associated marker expression.

Tinospora sinensis (Lour.) Merr. has traditionally been used for its anti-inflammatory properties. Tinosinenside A (Tis A), a major sesquiterpene glycoside isolated from this plant, has shown neuroprotective activity; however, its effects on Alzheimer's disease (AD)-related neuroinflammation remain unclear. This study evaluated the effects of Tis A on behavioral impairment, neuroinflammation, and amyloid-β (Aβ) pathology in APPswe/PSEN1dE9 (APP/PS1) mice. APP/PS1 mice received oral Tis A for 6 months and were evaluated at 11 months of age using behavioral, histopathological, biochemical, and molecular analyses. Tis A partially improved behavioral performance, reduced Aβ plaque burden and pro-inflammatory cytokine levels, attenuated microglial overactivation, shifted microglial phenotype-associated marker expression toward a less pro-inflammatory profile, and alleviated neuronal apoptosis and histopathological damage. These effects were accompanied by reduced TLR4 and NLRP3 inflammasome-related protein expression and decreased phosphorylation of NF-κB p65 and IκBα. Collectively, these findings indicate that Tis A attenuates neuroinflammation and AD-related neuropathology while providing partial behavioral benefits in APP/PS1 mice, supporting its further investigation as a natural-product-derived therapeutic lead for AD.