Methyl donor supplementation reduces phospho‐Tau, Fyn and demethylated PP2A levels, and mitigates learning and motor deficits in a mouse model of tauopathy

Reduced 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.Here, 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.TAU58/2 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.Our 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.