Methyl donor supplementation reduces phospho‐Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy

Abstract

AbstractBackgroundReduced folate status and elevated levels of circulating homocysteine are modifiable risk factors for cognitive decline and dementia. Disturbances in one‐carbon metabolism are associated with the pathological accumulation of phosphorylated tau, a hallmark feature of prevalent dementia, including Alzheimer's disease and subgroups of frontotemporal dementia.MethodsHere, using transgenic TAU58/2 mouse models of human tauopathy, we tested whether dietary supplementation with L‐methylfolate (the active folate form), choline and betaine can reduce tau phosphorylation and associated behavioural phenotypes.ResultsTAU58/2 mice fed with the methyl donor‐enriched diet showed reduced phosphorylation of tau at the pathological S202 (CP13) and S396/S404 (PHF‐1) epitopes and alleviation of associated motor and learning deficits. Compared with mice on the control diet, the decrease in cortical phosphorylated tau levels in mice fed with the methyl donor‐enriched diet was associated with enhanced methylation of protein phosphatase 2A, the major brain tau Ser/Thr phosphatase. It also correlated with a reduction in protein levels of Fyn, a tau tyrosine kinase that plays a central role in mediating pathological tau‐induced neurodegeneration. Conversely, Fyn expression levels were increased in mice with deficiencies in folate metabolism.ConclusionsOur findings provide the first experimental evidence that boosting one‐carbon metabolism with L‐methylfolate, choline and betaine can mitigate key pathological, learning and motor deficits in a tauopathy mouse model. They give support to using a combination of methyl donors as a preventive or disease‐modifying strategy for tauopathies.