Metformin treatment attenuates tau seeding in neuritic plaques

Background Alzheimer’s disease (AD) is characterized by deposition of amyloid‐β (Aβ) plaques, neurofibrillary tangles. Metformin has been reported to decrease Aβ plaque load , reduce spatial memory deficit in APP/PS1 mice and reduce tau phosphorylation in the P301S mutant human tau (P301S) transgenic mouse. However, the effect of metformin on Aβ plaque‐associated tau pathogies remains unclear. Method Female 9‐month‐old APPswe/PS1DE9(APP/PS1) mice were used. Mice in the treatment group received 4 mg/ml metformin in the drinking water for 2 months. Brain extract containing tau aggregates isolated from P301S transgenic mouse brain was unilaterally injected into the right hippocampus and overlying cerebral cortex two weeks after the initial administration of metformin. Tau pathology, its effect on Aβ pathology and plaque‐associated microgliosis were assessed by immunohistochemical staining and immunofluorescence analysis 50 days after infusion. Result We observed seeded tau aggregates in dystrophic neurites surrounding Aβ plaques(NP tau) throughout the ipsilateral hippocmapus as well as spread to the contralateral hippocmapus in seeded mice using this experimental paradigm. NP tau aggregation was reduced after metformin administration. We found a decrease in the number of microglia around Aβ plaques in hippocampus of seeded mice and an increase of Aβ load in the bilateral cortex and the ipsilateral dentate gyrus of hippocampus in seeded mice. Metformin administration enhanced the activation of microglia around Aβ plaques and attenuates the Aβ load in the seeded mice. Conclusion These findings indicate that metformin can enhance plaque‐associated microgliosis, attenuate Aβ load and peri‐plaque tau pathologies, making it a potential therapeutic treatment for AD.