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Cited by 111Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

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Chen, Yanxing, Zhao, Shuai, Fan, Ziqi, Li, Zheyu, Zhu, Yueli, Shen, Ting, Li, Kaicheng, Yan, Yaping +3 more·2021·Alzheimer's Research & Therapy
DOI 10.1186/s13195-020-00761-9PMC PMC7871393
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Abstract

Background: The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. Methods: Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. Results: We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice. Conclusion: These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

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  • In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neurites.

    “In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neuritis [13, 53, 106], which subsequently contributes to the formation of neuritic plaques (a subset of Aβ plaques surrounded by and containing dystrophic neurites) during AD progression”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [13]

    The Discussion (page unavailable) reports tau aggregation in dystrophic neurites surrounding Aβ plaques, and the Introduction reports enhanced tau phosphorylation in a mouse model with amyloid pathology. The paper does not establish that filamentous plaques form in association with this phosphorylation, nor does it extend that finding to aging generally. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Phosphorylation of tau within dystrophic neurites subsequently contributes to the formation of neuritic plaques during AD progression.

    “In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neuritis [13, 53, 106], which subsequently contributes to the formation of neuritic plaques (a subset of Aβ plaques surrounded by and containing dystrophic neurites) during AD progression”

    From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [13]

    The Results report phosphorylated tau particles surrounding Aβ plaques in APP/PS1 mice, supporting the association between tau pathology and plaques. The Discussion instead proposes that existing Aβ plaques induce tau accumulation in surrounding dystrophic neurites; it does not establish that tau phosphorylation forms neuritic plaques during AD progression. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Chen, Y., Zhao, S., Fan, Z., Li, Z., Zhu, Y., Shen, T., Li, K., Yan, Y., Tian, J., Liu, Z., & Zhang, B.
Affiliations
Second Affiliated Hospital of Zhejiang University (CN)
Corresponding author
Zhang, Baorong
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-02-09
Volume
13
Issue
1
Pages
40-40
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-020-00761-9
PMC
PMC7871393
OpenAlex
W3127018987
Cited by
111
References
16
Citations by year
2026: 14 · 2025: 17 · 2024: 26 · 2023: 22 · 2022: 26 · 2021: 6
FWCI
12.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81520108010, 81870826)
  • Natural Science Foundation of Zhejiang Province (LY18H090004, LY17H090003)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
metformin, Alzheimer's disease, amyloid plaques, tau pathology, APP/PS1 mice, microglial activation, neurofibrillary tangles, dystrophic neurites, neuroinflammation
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Metformin, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Mice, Presenilin-1, Plaque, Amyloid

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