Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway

自噬 厚朴酚 安普克 PI3K/AKT/mTOR通路 ULK1 细胞生物学 雷帕霉素的作用靶点 蛋白激酶A 化学 癌症研究 激酶 细胞凋亡 信号转导 生物 药理学 生物化学
作者
Xuechu Wang,Jianping Jia
出处
期刊:Biomedicine & Pharmacotherapy [Elsevier]
卷期号:161: 114473-114473 被引量:21
标识
DOI:10.1016/j.biopha.2023.114473
摘要

Alzheimer's disease (AD) is the most common neurodegenerative disease. Amyloid-β (Aβ) plaque deposition and apoptosis are main pathological features of AD. Autophagy plays an important role in clearing abnormal protein accumulation and inhibiting apoptosis; however, autophagy defects often occur from the early stages of AD. The serine/threonine AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1/2 (ULK1/2) pathway serves as an energy sensor and is involved in autophagy activation. Furthermore, magnolol is an autophagy regulator, and has potential for AD therapy. We propose that magnolol can ameliorate AD pathologies and inhibit apoptosis by regulating autophagy through the AMPK/mTOR/ULK1 pathway. We examined cognitive function and AD-related pathologies in AD transgenic mice and the protective mechanism of magnolol by western blotting, flow cytometry, and a tandem mRFP-GFP-LC3 adenovirus assay in Aβ oligomer (AβO)-induced N2a and BV2 cell models. In our study, magnolol decreased amyloid pathology and ameliorated cognitive impairment in APP/PS1 mice. Moreover, magnolol inhibited apoptosis by downregulating cleaved-caspase-9 and Bax and upregulating Bcl-2 in APP/PS1 mice and AβO-induced cell models. Magnolol promoted autophagy by degrading p62/SQSTM1, and upregulating LC3II and Beclin-1 expression. Magnolol activated the AMPK/mTOR/ULK1 pathway by increasing phosphorylation of AMPK and ULK1 and decreasing mTOR phosphorylation in in vivo and in vitro AD models. AMPK inhibitor weakened the effects of magnolol in promoting autophagy and inhibiting apoptosis, and ULK1 knockdown weakened the effect of magnolol on AβO-induced apoptosis. These results indicate that magnolol inhibits apoptosis and improves AD-related pathologies by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.
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