Effect of Metformin on tau pathology and proteostasis in cellular and a Drosophila model of Tauopathy

Abstract Alzheimer’s disease is increasingly linked to metabolic dysfunction, with insulin resistance emerging as a key contributor to tau pathology. The antidiabetic drug Metformin has shown conflicting effects in neurodegeneration, underscoring the need to resolve its mechanistic impact on tau regulation. This study combines insulin-resistant neuroblastoma cells with Drosophila models of tauopathy to define how Metformin modulates tau phosphorylation via underlying signalling pathways. Metformin treatment increased total tau levels while consistently reducing hyperphosphorylated tau at disease-relevant epitopes in endogenous neuroblastoma cells. This dissociation was associated with enhanced activation of AKT and AMPK signalling and maintenance of basal phosphatase activity. We further observed that Metformin at low concentrations promoted autophagic activity, whereas higher concentrations impaired autophagic clearance. In the Tauopathy models, Metformin selectively ameliorated tau-induced neurodegeneration and tau-hyperphosphorylation in tau-0N4R but not in more pathogenic tau variants (tau-2N4R and tau-E14). The alteration in pathological tau levels did not correlate directly with the status of autophagy. On the contrary, autophagic status was influenced by diet and sex of these organisms. Together, our findings demonstrate that Metformin modulates tau phosphorylation independently of total tau levels and reveals a critical dissociation between upstream metabolic signalling and downstream proteostatic outcomes.