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Cited by 171Autophagy in Disease and TherapyAlzheimer's disease research and treatmentsHeat shock proteins research

Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

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Xu, Xiaoyan, Sun, Yaqin, Cen, Xufeng, Shan, Bing, Zhao, Qingwei, Xie, Tingxue, Wang, Zhe, Hou, Tingjun +7 more·2021·Protein & Cell
DOI 10.1007/s13238-021-00858-3PMC PMC8464644
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Abstract

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-IKKα/β 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 IKKα/β-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 Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.

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  • CMA is a selective autophagy mechanism disrupted early in Alzheimer's disease, partly due to reduced LAMP2A expression.

    “CMA is increasingly recognized as a selective mechanism disrupted early in AD, partly due to reduced LAMP2A expression [140, 141].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [141]

    The Introduction describes CMA as selective and says AD-associated Tau can suppress it by binding to LAMP2A. The Discussion also calls compromised CMA a feature of AD. Neither section establishes that the disruption occurs early in AD or attributes it to reduced LAMP2A expression; the paper describes disrupted LAMP2A-mediated translocation instead. Page numbers are not available in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Defective CMA reduces degradation of tau and α-synuclein, increasing aggregation-prone species.

    “Third, defective CMA reduces the degradation of tau and α-synuclein, increasing aggregation-prone species [140, 141].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [141]

    The Introduction and the Results section 'APP is a CMA substrate' state that CMA can degrade tau. They also say that aggregated tau can inhibit CMA, rather than establishing that defective CMA increases tau aggregation. No passage in our copy addresses α-synuclein degradation or aggregation (searched: α-synuclein, synuclein). Page numbers were not available. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Xu, X., Sun, Y., Cen, X., Shan, B., Zhao, Q., Xie, T., Wang, Z., Hou, T., Xue, Y., Zhang, M., Peng, D., Sun, Q., Yi, C., Najafov, A., & Xia, H.
Affiliations
  • First Affiliated Hospital Zhejiang University (CN)
  • Chinese Academy of Sciences (CN)
  • Zhejiang University (CN)
  • Huazhong University of Science and Technology (CN)
  • Harvard University (US)
Corresponding author
  • Najafov, Ayaz
  • Xia, Hongguang
ORCID
Venue
Protein & Cell
Publisher
Oxford University Press (OUP)
Published
2021-07-21
Volume
12
Issue
10
Pages
769-787
ISSN
  • 1674-800X (ISSN-L)
  • 1674-8018
DOI
10.1007/s13238-021-00858-3
PMC
PMC8464644
OpenAlex
W3186382490
Cited by
171
References
12
Citations by year
2026: 24 · 2025: 49 · 2024: 37 · 2023: 30 · 2022: 27 · 2021: 3
FWCI
17.15
Type
journal article
Language
en
Update notices
correction (2021-11-01)
Open access
Licence
Locations
  • Protein & Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81773182 and 31601121, 31601121, 81773182, 91854108)
  • Chinese Academy of Sciences
  • Zhejiang University
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
chaperone-mediated autophagy, metformin, Alzheimer's disease, Hsc70, TAK1, amyloid precursor protein, amyloid plaques, APP/PS1 mice, drug repurposing, lysosomal degradation
MeSH terms
Chaperone-Mediated Autophagy, MAP Kinase Kinase Kinase 7, Alzheimer Disease, Animals, Benzylamines, Disease Models, Animal, Gene Expression Regulation, HeLa Cells, Humans, Isoenzymes, Male, Metformin, Mice, Transgenic, Neurons, Phenylurea Compounds, Quinazolines, Signal Transduction, Amyloid beta-Protein Precursor, PC12 Cells, Neuroprotective Agents, MAP Kinase Kinase Kinases, Cell Line, Tumor, HSC70 Heat-Shock Proteins, Mice, Rats, I-kappa B Kinase, Benzothiazoles, HEK293 Cells

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