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. 2021 Feb 9;13(1):40.
doi: 10.1186/s13195-020-00761-9.

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

Yanxing Chen #  1 , Shuai Zhao #  1 , Ziqi Fan  1 , Zheyu Li  1 , Yueli Zhu  1   2 , Ting Shen  1 , Kaicheng Li  1 , Yaping Yan  1 , Jun Tian  1 , Zhirong Liu  1 , Baorong Zhang  3
Affiliations

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

Yanxing Chen et al. Alzheimers Res Ther. .

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.

Keywords: Alzheimer’ disease; Aβ pathology; Metformin; Microglia; Spread; Tau pathology.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic illustrations of injection sites with coronal planes. a Study design. b Red dotted line indicates injection path and white arrowheads indicate injection site
Fig. 2
Fig. 2
Injection of proteopathic tau seeds induced NP tau aggregation in APP/PS1 mice. a–d Representative images of co-staining for 6E10 (green), AT8 (red) in the hippocampus, and cortex of PS19BE-injected APP/PS1 mice (a, b), WTBE-injected APP/PS1 mice (c), and PS19BE-injected WT mice (d). Partial magnifications are shown. Scale bar, 100 μm
Fig. 3
Fig. 3
Metformin reduced NP tau aggregation in PS19BE-injected APP/PS1 mice. a Representative images of NP tau burden labeled with AT8 (a), AT180 (b), or p-Tau 422 (c) surrounding Aβ burden labeled with 6E10 (a) or 4G8 (b, c) in PS19BE-injected APP/PS1 mice treated with or without metformin. Scale bars, 50 μm. d–f Quantification of NP tau in PS19BE-injected APP/PS1 mice treated with or without metformin. Data were analyzed by Student’s t test. Values are presented as mean±SEM. n = 5 per group. #P < 0.05 vs. tau+veh group
Fig. 4
Fig. 4
Immunohistochemical analysis of Aβ burden in cortex of APP/PS1 mice. a Representative images of 6E10-labeled Aβ burden in the ipsilateral and contralateral cortices of APP/PS1 mice. Scale bars, 200 μm. b, c Quantification of percent area covered by 6E10 staining in the ipsilateral cortex (b) and contralateral cortex (c) of the APP/PS1 mice. Data were analyzed by one-way ANOVA followed by the Bonferroni post hoc test. Values are presented as mean±SEM. n = 5 per group. *P < 0.05 vs. ctr+veh group; #P < 0.05 vs. tau+veh group; &P < 0.05 vs. ctr+met group
Fig. 5
Fig. 5
Immunohistochemical analysis of Aβ burden in hippocampus of APP/PS1 mice. a Representative images of 6E10-labeled Aβ burden in the ipsilateral and contralateral hippocampus of APP/PS1 mice. Scale bars, 200 μm. b, c Quantification of percent area covered by 6E10 staining in the ipsilateral hippocampus (hpx) (b) and contralateral hippocampus (c) of the APP/PS1 mice. d–i Quantification of percent area covered by 6E10 staining in the ipsilateral DG (d), CA3 (f), CA1 (h), contralateral DG (e), CA3 (g), and CA1 (i) of the hippocampi of APP/PS1 mice. Data were analyzed by one-way ANOVA followed by the Bonferroni post hoc test. Values are presented as mean±SEM. n = 5 per group. *P < 0.05 vs. ctr+veh group; #P < 0.05 vs. tau+veh group; &P < 0.05 vs. ctr+met group
Fig. 6
Fig. 6
Immunofluorescence analysis of microglia in relation with Aβ plaques and NP tau pathologies in APP/PS1 mice. a Representative confocal images of Iba1+ microglia (green) surrounding 6E10+ Aβ plaques (red) in the brains of APP/PS1 mice. Scale bars, 100 μm. b Quantification of the number of microglial cells surrounding plaques in APP/PS1 mice. Data were analyzed by one-way ANOVA followed by the Bonferroni post hoc test. Values are presented as mean±SEM. n = 5 per group. *P < 0.05 vs. ctr+veh group; #P < 0.05 vs. tau+veh group; &P < 0.05 vs. ctr+met group. c Representative confocal images of Iba1+ microglia (green) and AT8+ NP tau (red) in the brains of APP/PS1 mice. Scale bars, 50 μm. d Percentage of AT8+ microglial cells with respect to total Iba1+ microglial cells in the in PS19BE-injected APP/PS1 mice treated with or without metformin. Data were analyzed by Student’s t test. Values are presented as mean±SEM. n = 5 per group. #P < 0.05 vs. tau+veh group
Fig. 7
Fig. 7
Metformin reduced accumulation of autophagy-related protein in microglia in APP/PS1 mice. a Representative images of p62+ aggregates (green) in the brains of APP/PS1mice. Scale bars, 50 μm. b Confocal images of Iba1+ microglia (red) and p62+ aggregates (green) in the brains of APP/PS1 mice. Scale bars, 50 μm. c Quantification of percent area covered by p62 staining in APP/PS1 mice. Data were analyzed by one-way ANOVA followed by the Bonferroni post hoc test. Values are presented as mean±SEM. n = 5 per group. d, e Quantitative analysis of p62+ aggregates in microglia, expressed as the percentage of Iba1+ area that is also p62+ (d) and the percentage of the number of Iba1+ microglia containing p62+ aggregates (e). Data were analyzed by one-way ANOVA followed by the Bonferroni post hoc test. Values are presented as mean±SEM. n = 5 per group. *P < 0.05 vs. ctr+veh group; #P < 0.05 vs. tau+veh group; &P < 0.05 vs. ctr+met group
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