PMID- 36889111 OWN - NLM STAT- MEDLINE DCOM- 20230404 LR - 20230404 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 161 DP - 2023 May TI - Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway. PG - 114473 LID - S0753-3322(23)00261-5 [pii] LID - 10.1016/j.biopha.2023.114473 [doi] AB - Alzheimer's disease (AD) is the most common neurodegenerative disease. Amyloid-beta (Abeta) 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 Abeta oligomer (AbetaO)-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 AbetaO-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 AbetaO-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. CI - Copyright (c) 2023. Published by Elsevier Masson SAS. FAU - Wang, Xuechu AU - Wang X AD - Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, PR China. FAU - Jia, Jianping AU - Jia J AD - Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, PR China; Beijing Key Laboratory of Geriatric Cognitive Disorders, PR China; Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, PR China; Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, PR China; Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing 100053, PR China. Electronic address: jiajp@vip.126.com. LA - eng PT - Journal Article DEP - 20230306 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - 001E35HGVF (magnolol) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ulk1 protein, mouse) RN - EC 2.7.1.1 (mTOR protein, mouse) SB - IM MH - Animals MH - Mice MH - *Alzheimer Disease/drug therapy/metabolism MH - AMP-Activated Protein Kinases/metabolism MH - Autophagy MH - *Cognitive Dysfunction/drug therapy MH - Mammals MH - Mice, Transgenic MH - *Neurodegenerative Diseases MH - Protein Serine-Threonine Kinases MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - Alzheimer's disease OT - Apoptosis OT - Autophagy OT - Magnolol COIS- Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/03/09 06:00 MHDA- 2023/04/03 06:41 CRDT- 2023/03/08 18:08 PHST- 2023/01/22 00:00 [received] PHST- 2023/02/27 00:00 [revised] PHST- 2023/03/02 00:00 [accepted] PHST- 2023/04/03 06:41 [medline] PHST- 2023/03/09 06:00 [pubmed] PHST- 2023/03/08 18:08 [entrez] AID - S0753-3322(23)00261-5 [pii] AID - 10.1016/j.biopha.2023.114473 [doi] PST - ppublish SO - Biomed Pharmacother. 2023 May;161:114473. doi: 10.1016/j.biopha.2023.114473. Epub 2023 Mar 6.