Abstract
BackgroundAlzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological and experimental evidence suggests a clear link between type 2 diabetes mellitus and AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy. However, their efficacy for tauopathy in vivo has not been tested.ResultsHere, we report that in the P301S mutant human tau (P301S) transgenic mouse model of tauopathy, chronic administration of metformin exerts paradoxical effects on tau pathology. Despite reducing tau phosphorylation in the cortex and hippocampus via AMPK/mTOR and PP2A, metformin increases insoluble tau species (including tau oligomers) and the number of inclusions with β-sheet aggregates in the brain of P301S mice. In addition, metformin exacerbates hindlimb atrophy, increases P301S hyperactive behavior, induces tau cleavage by caspase 3 and disrupts synaptic structures.ConclusionsThese findings indicate that metformin pro-aggregation effects mitigate the potential benefits arising from its dephosphorylating action, possibly leading to an overall increase of the risk of tauopathy in elderly diabetic patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0082-7) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau
S16H-Rheb expression abolished metformin-induced tau dephosphorylation (Fig. 4i), without affecting tau expression levels (Additional file 1: Figure S3G). These results indicate that the effects of metformin on tau phosphorylation occur in an insulinindependent manner and require the activity of AMP-activated protein kinase (AMPK) and phosphatase 2A (PP2A) and inhibition of mammalian target of rapamycin (mTOR)
Our results indicate that the effects of metformin on tau pathology manifest at doses yielding serum concentrations consistent with those of therapeutic dosing in humans [22]
Summary
Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy. Anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy Their efficacy for tauopathy in vivo has not been tested. The progression of cerebral tau pathology appears to be influenced by several risk factors and comorbidities, including diabetes and insulin resistance. Molecular markers of insulin resistance co-localize with tau inclusions in AD brain [7], suggesting that impaired
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