PMID- 34291435
OWN - NLM
STAT- MEDLINE
DCOM- 20220126
LR  - 20220126
IS  - 1674-8018 (Electronic)
IS  - 1674-800X (Print)
IS  - 1674-800X (Linking)
VI  - 12
IP  - 10
DP  - 2021 Oct
TI  - Metformin activates chaperone-mediated autophagy and improves disease pathologies 
      in an Alzheimer disease mouse model.
PG  - 769-787
LID - 10.1007/s13238-021-00858-3 [doi]
AB  - Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation 
      pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. 
      However, the mechanisms that regulate CMA are not fully understood. Here, using 
      unbiased drug screening approaches, we discover Metformin, a drug that is 
      commonly the first medication prescribed for type 2 diabetes, can induce CMA. We 
      delineate the mechanism of CMA induction by Metformin to be via activation of 
      TAK1-IKKalpha/beta signaling that leads to phosphorylation of Ser85 of the key mediator 
      of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor 
      protein (APP) is a CMA substrate and that it binds to Hsc70 in an 
      IKKalpha/beta-dependent manner. The inhibition of CMA-mediated degradation of APP 
      enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model 
      of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or 
      Metformin potently reduces the accumulated brain Abeta plaque levels and reverses 
      the molecular and behavioral AD phenotypes. Our study elucidates a novel 
      mechanism of CMA regulation via Metformin-TAK1-IKKalpha/beta-Hsc70 signaling and 
      suggests Metformin as a new activator of CMA for diseases, such as AD, where such 
      therapeutic intervention could be beneficial.
CI  - (c) 2021. The Author(s).
FAU - Xu, Xiaoyan
AU  - Xu X
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
AD  - Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
FAU - Sun, Yaqin
AU  - Sun Y
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
FAU - Cen, Xufeng
AU  - Cen X
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
FAU - Shan, Bing
AU  - Shan B
AD  - Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China.
FAU - Zhao, Qingwei
AU  - Zhao Q
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
FAU - Xie, Tingxue
AU  - Xie T
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
FAU - Wang, Zhe
AU  - Wang Z
AD  - College of Pharmaceutical Sciences, Hangzhou Institute of innovative Medicine, 
      Zhejiang University, Hangzhou, 310058, China.
FAU - Hou, Tingjun
AU  - Hou T
AD  - College of Pharmaceutical Sciences, Hangzhou Institute of innovative Medicine, 
      Zhejiang University, Hangzhou, 310058, China.
FAU - Xue, Yu
AU  - Xue Y
AD  - Key Laboratory of Molecular Biophysics of Ministry of Education, Hubei 
      Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and 
      Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
FAU - Zhang, Mengmeng
AU  - Zhang M
AD  - Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of 
      Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201203, China.
FAU - Peng, Di
AU  - Peng D
AD  - Key Laboratory of Molecular Biophysics of Ministry of Education, Hubei 
      Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and 
      Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
FAU - Sun, Qiming
AU  - Sun Q
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
FAU - Yi, Cong
AU  - Yi C
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China.
FAU - Najafov, Ayaz
AU  - Najafov A
AD  - Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. 
      najafov@gmail.com.
FAU - Xia, Hongguang
AU  - Xia H
AUID- ORCID: 0000-0003-3044-9282
AD  - Department of Biochemistry & Research Center of Clinical Pharmacy of The First 
      Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, 
      China. hongguangxia@zju.edu.cn.
AD  - Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China. 
      hongguangxia@zju.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210721
PL  - Germany
TA  - Protein Cell
JT  - Protein & cell
JID - 101532368
RN  - 0 (APP protein, mouse)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Benzothiazoles)
RN  - 0 (Benzylamines)
RN  - 0 (HSC70 Heat-Shock Proteins)
RN  - 0 (Hspa8 protein, mouse)
RN  - 0 (Isoenzymes)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Quinazolines)
RN  - 0 (spautin-1)
RN  - 7LA4O6Q0D3 (quizartinib)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP kinase kinase kinase 7)
SB  - IM
EIN - Protein Cell. 2022 Mar;13(3):227-229. PMID: 34725788
MH  - Alzheimer Disease/*drug therapy/genetics/metabolism/pathology
MH  - Amyloid beta-Protein Precursor/*genetics/metabolism
MH  - Animals
MH  - Benzothiazoles/pharmacology
MH  - Benzylamines/pharmacology
MH  - Cell Line, Tumor
MH  - Chaperone-Mediated Autophagy/*drug effects/genetics
MH  - Disease Models, Animal
MH  - Gene Expression Regulation
MH  - HEK293 Cells
MH  - HSC70 Heat-Shock Proteins/*genetics/metabolism
MH  - HeLa Cells
MH  - Humans
MH  - I-kappa B Kinase/genetics/metabolism
MH  - Isoenzymes/genetics/metabolism
MH  - MAP Kinase Kinase Kinases/*genetics/metabolism
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurons/drug effects/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - PC12 Cells
MH  - Phenylurea Compounds/pharmacology
MH  - Quinazolines/pharmacology
MH  - Rats
MH  - Signal Transduction
PMC - PMC8464644
OTO - NOTNLM
OT  - APP
OT  - Alzheimer's disease
OT  - Hsc70
OT  - IKKalpha/beta
OT  - Metformin
OT  - TAK1
OT  - chaperone-mediated autophagy
COIS- The authors have no conflicts of interest to declare that are relevant to the 
      content of this article.
EDAT- 2021/07/23 06:00
MHDA- 2022/01/27 06:00
PMCR- 2021/07/21
CRDT- 2021/07/22 06:47
PHST- 2021/04/28 00:00 [received]
PHST- 2021/06/03 00:00 [accepted]
PHST- 2021/07/23 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/07/22 06:47 [entrez]
PHST- 2021/07/21 00:00 [pmc-release]
AID - 10.1007/s13238-021-00858-3 [pii]
AID - 858 [pii]
AID - 10.1007/s13238-021-00858-3 [doi]
PST - ppublish
SO  - Protein Cell. 2021 Oct;12(10):769-787. doi: 10.1007/s13238-021-00858-3. Epub 2021 
      Jul 21.