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

Background The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-beta (A beta) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. A beta deposition precedes the aggregation of tau pathology and A beta 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. A beta 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 A beta plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. A beta plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated A beta deposits and decreased the number of microglia around A beta plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around A beta plaques, promoted the phagocytosis of NP tau, and reduced A beta 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 A beta and tau proteins by enhancing microglial autophagy capability. It reduced A beta deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

Automated summary

The study uncovered a crosstalk between amyloid and NP tau pathology, where Aβ plaques promoted the aggregation of NP tau, and metformin enhanced microglial autophagy capability to promote the phagocytosis of pathological Aβ and tau proteins, reducing Aβ deposits and limiting the spreading of NP tau pathology.