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Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice.
Alzheimers Res Ther. 2021 02 09; 13(1):40.AR

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.

Authors+Show Affiliations

Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China. Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.Department of Neurology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China. brzhang@zju.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33563332

Citation

Chen, Yanxing, et al. "Metformin Attenuates Plaque-associated Tau Pathology and Reduces Amyloid-β Burden in APP/PS1 Mice." Alzheimer's Research & Therapy, vol. 13, no. 1, 2021, p. 40.
Chen Y, Zhao S, Fan Z, et al. Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice. Alzheimers Res Ther. 2021;13(1):40.
Chen, Y., Zhao, S., Fan, Z., Li, Z., Zhu, Y., Shen, T., Li, K., Yan, Y., Tian, J., Liu, Z., & Zhang, B. (2021). Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice. Alzheimer's Research & Therapy, 13(1), 40. https://doi.org/10.1186/s13195-020-00761-9
Chen Y, et al. Metformin Attenuates Plaque-associated Tau Pathology and Reduces Amyloid-β Burden in APP/PS1 Mice. Alzheimers Res Ther. 2021 02 9;13(1):40. PubMed PMID: 33563332.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice. AU - Chen,Yanxing, AU - Zhao,Shuai, AU - Fan,Ziqi, AU - Li,Zheyu, AU - Zhu,Yueli, AU - Shen,Ting, AU - Li,Kaicheng, AU - Yan,Yaping, AU - Tian,Jun, AU - Liu,Zhirong, AU - Zhang,Baorong, Y1 - 2021/02/09/ PY - 2020/10/21/received PY - 2020/12/23/accepted PY - 2021/2/10/entrez PY - 2021/2/11/pubmed PY - 2021/6/25/medline KW - Alzheimer’ disease KW - Aβ pathology KW - Metformin KW - Microglia KW - Spread KW - Tau pathology SP - 40 EP - 40 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 13 IS - 1 N2 - 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. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/33563332/Metformin_attenuates_plaque_associated_tau_pathology_and_reduces_amyloid_β_burden_in_APP/PS1_mice_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-020-00761-9 DB - PRIME DP - Unbound Medicine ER -