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Resveratrol Attenuates Aβ25–35 Caused Neurotoxicity by Inducing Autophagy Through the TyrRS-PARP1-SIRT1 Signaling Pathway

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of β-amyloid peptide (Aβ) and loss of neurons. Resveratrol (RSV) is a natural polyphenol that has been found to be beneficial for AD through attenuation of Aβ-induced toxicity in neurons both in vivo and in vitro. However, the specific underlying mechanisms remain unknown. Recently, autophagy was found to protect neurons from toxicity injuries via degradation of impaired proteins and organelles. Therefore, the aim of this study was to determine the role of autophagy in the anti-neurotoxicity effect of RSV in PC12 cells. We found that RSV pretreatment suppressed β-amyloid protein fragment 25–35 (Aβ25–35)-induced decrease in cell viability. Expression of light chain 3-II, degradation of sequestosome 1, and formation of autophagosomes were also upregulated by RSV. Suppression of autophagy by 3-methyladenine abolished the favorable effects of RSV on Aβ25–35-induced neurotoxicity. Furthermore, RSV promoted the expression of sirtuin 1 (SIRT1), auto-poly-ADP-ribosylation of poly (ADP-ribose) polymerase 1 (PARP1), as well as tyrosyl transfer-RNA (tRNA) synthetase (TyrRS). Nevertheless, RSV-mediated autophagy was markedly abolished with the addition of inhibitors of SIRT1 (EX527), nicotinamide phosphoribosyltransferase (STF-118804), PARP1 (AG-14361), as well as SIRT1 and TyrRS small interfering RNA transfection, indicating that the action of RSV on autophagy induction was dependent on TyrRS, PARP1 and SIRT1. In conclusion, RSV attenuated neurotoxicity caused by Aβ25–35 through inducing autophagy in PC12 cells, and the autophagy was partially mediated via activation of the TyrRS-PARP1-SIRT1 signaling pathway.

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Abbreviations

3-MA:

3-methyladenine

AD:

Alzheimer’s disease

Aβ:

β-amyloid peptide

Aβ25–35 :

β-amyloid protein fragment 25–35

CCK-8:

Cell counting kit-8

LC3:

Light chain 3

NAD+ :

Nicotinamide adenine dinucleotide

NAMPT:

Nicotinamide phosphoribosyltransferase

PARP1:

Auto-poly-ADP-ribosylation of poly (ADP-ribose) polymerase 1

p62:

Sequestosome 1

RSV:

Resveratrol

siRNA:

Small interfering RNA

SIRT1:

Sirtuin 1

TyrRS:

Tyrosyl transfer-RNA (tRNA) synthetase

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Acknowledgments

We are particularly grateful to Dr. Mingliang Chen (Third Military Medical University) for his critical review and valuable suggestions that greatly improved the quality of this manuscript.

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  1. Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People’s Republic of China

    Haoyue Deng & Man-tian Mi

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Correspondence to Man-tian Mi.

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Deng, H., Mi, Mt. Resveratrol Attenuates Aβ25–35 Caused Neurotoxicity by Inducing Autophagy Through the TyrRS-PARP1-SIRT1 Signaling Pathway. Neurochem Res 41, 2367–2379 (2016). https://doi.org/10.1007/s11064-016-1950-9

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