The Role Of Metformin On The Spreading Of Tau And Amyloid-β Pathologies In Alzheimer’s Disease And The Underlying Mechanisms

Chapter 1 Metformin attenuates tau spreading and ameliorates cognitive deficit in PS19 miceBackground Accumulation of Neurofibrillary tangles(NFTs)composed of hyperphosphorylated tau is one of the histopathological hallmarks of Alzheimer’s Disease(AD)and related tauopathies.Accumulating evidence demonstrated that tau aggregates can recruit monomeric tau into fibrillar aggregates,which further spread to other brain regions.Metformin might have a positive effect on cognitive impairments.However,the effect of metformin on tau propagation remains unclear.Methods Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of PS19 mice.Metformin was administrated in the drinking water for 4 months.Tau pathology was analyzed by immunofluorescence analysis.The effects of metformin on the phosphorylation of tau protein,tau phosphatases and tau kinases were determined by Western blot.The cognitive function of the mice was examined by Morris Water Maze.Results We observed propagation of tau pathology in the brains of tau-injected PS19 mice.Metformin reduced spreading of tau pathology,decreased the hyperphosphorylation of tau protein at AT8,Thr231 and Ser422 sites in the soluble fraction,decreased the hyperphosphorylation of tau protein at AT8,Ser262,Thr396,Thr231 and Ser422 sites in the insoluble fraction of the brains of tau-injected PS19 mice.Metformin increased the activity of PP2 A but had no effects on tau kinases.Metformin attenuated learning and memory deficits in tau-injected PS19 mice.Conclusions The results indicate that metformin decreased the hyperphosphorylation of tau protein,attenuated the spreading of tau pathology and improved the behavioral performance in tau-injected PS19 mice,which exerts a beneficial effect on PS19 mice.Chapter 2 Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 miceBackground 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 ADrelated 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.Conclusions These findings indicate the existence of the cross talk 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.