Piperlongumine activates Sirtuin1 and improves cognitive function in a murine model of Alzheimer's disease

Sirtuinl (Sirt1) is an unusual target for aging and aging-associated diseases. During the screening for Sirt1 activators from natural compounds, piperlongumine (PL), one of the major constituents of Piper longum, potently activated the deacetylase ability of Sirt1 in vitro. Treatment with PL, which regulated the gene transcription of antioxidant response element in hippocampal neurons, attenuated the cytotoxicity induced by intraneuronal A beta(1-42) expression. The oral administration of PL, at a dose of 50 mg/kg/day for 2.5 months, significantly reduced the occupied area of beta-amyloid in parietal cortex of APP/PS1 mice. Novel object recognition and working memory impairment also markedly improved. Moreover, activated microglia and astrocytes in the cortex notably decreased, indicating the anti-inflammatory activity of PL. Finally, vesicular glutamate transporter 1 significantly increased in the hippocampus of APP/PS1 mice following PL treatment. These results suggested the beneficial effects PL and its therapeutic potential to ameliorate AD-like pathology.