N-linoleyltyrosine protects neurons against Aβ1–40-induced cell toxicity via autophagy involving the CB2/AMPK/mTOR/ULK1 pathway

Abstract

Beta-amyloid protein (Aβ) is one of the most important pathogenic factors of Alzheimer’s disease (AD). N-linoleyltyrosine (NITyr) was synthesized in our laboratory and exerted neuroprotective effects in APP/PS1 transgenic mice in previous reports. In this study, the neuroprotective effects and mechanisms of NITyr were evaluated in Aβ1–40-treated primary cortical neurons for the first time in vitro. NITyr treatment attenuated cytotoxicity induced by Aβ1–40, and the best effect of NITyr was observed at 1 μmol/L. NITyr treatment increased the BDNF protein expression and the ratio of p-CREB/CREB, but weakened the Caspase-3 protein expression. Meanwhile, NITyr enhanced the expressions of autophagy-related proteins (LC3-II, Beclin-1, ATG5 and ATG13). The autophagy inhibitor 3-methyladenine (3MA) reversed the effects of NITyr on cell viability and the protein expressions of neuron-related proteins, including BDNF, p-CREB and Caspase-3. The CB2 receptor antagonist AM630 weakened the neuroprotective effects of NITyr and the autophagy-related protein expression (LC3-II, Beclin-1, ATG5 and ATG13). Moreover, NITyr significantly increased the expressions of p-AMPK, p-mTOR and p-ULK1, but not p-p38. AM630 ablated the above phenomenon. Therefore, NITyr protected the neurons against Aβ1–40-induced cytotoxicity by inducing autophagy, which involved the CB2/AMPK/mTOR/ULK1 pathway.

Keywords

• N-linoleyltyrosine
• Cannabinoid receptor
• Autophagy
• Beta-amyloid protein
• Neuron