Attenuation of Pb-induced Aβ generation and autophagic dysfunction via activation of SIRT1: Neuroprotective properties of resveratrol

This study examined the neuroprotective properties of resveratrol (Res) and its target sirtuin1 (SIRT1) against lead (Pb)-mediated toxicity and discovered that both resveratrol treatment and SIRT1 overexpression restored blocked autophagic flux as well as reduced beta-amyloid (A beta) contents. Four-week-old male C57BL/6 mice were employed to consumed 0.2% Pb(Ac)(2) solution or deionized water for 3 months followed by 12 months of Res (50 mg/kg BW) or vehicle gavage. In in vitro study, SH-SY5Y cells were pretreated with the SIRT1 activator SRT1720 (2 mu M) or the inhibitor EX527 (2 mu M) for 2 h, then 25 mu M of Pb(Ac)(2) was added and incubated for 48 h. Western blotting, RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and Lyso-Tracker Red Staining were next used to estimate the potential alterations of the autophagic pathway as well as BACE1-mediated amyloid processing in response to Pb exposure, respectively. Our data revealed that Res treatment or SIRT1 activation resisted the induction of autophagy by Pb exposure through inhibition of LC3 and Beclin-1 expression and promoted the degradation of A beta and Tau phosphorylation. Besides, the SIRT1 activator (SRT1720) downregulated the expression of BACE1, the rate-limiting enzyme for A beta production, by inhibiting the activation of nuclear factor kappa B (NF-kappa B) in Pb-treated SH-SY5Y cells, which resulted in reduced A beta production. Collectively, we verified the role of Res-SIRT1-autophagy as well as the SIRT1-NF-kappa B-BACE1 pathway in Pb-induced neuronal cell injury by in vivo or in vitro models. Our findings further elucidate the important role of SIRT1 and Res in counteracting Pb neurotoxicity, which may provide new interventions and targets for the subsequent treatment of neurodegenerative diseases.

Automated summary

The study demonstrated the neuroprotective effects of resveratrol and SIRT1 against lead toxicity by restoring autophagic flux and reducing Aβ contents. Resveratrol treatment and SIRT1 overexpression inhibited the induction of autophagy by lead exposure and promoted the degradation of Aβ and Tau phosphorylation. Additionally, SIRT1 activation downregulated BACE1 expression by inhibiting NF-κB activation, leading to reduced Aβ production.