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

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Annika van Hummel, Goce Taleski, Jean-Marie Sontag, Astrid Feentje Feiten, Yazi D Ke, Lars M Ittner, Estelle Sontag
• Journal: Neuropathology and applied neurobiology (Neuropathol Appl Neurobiol) Vol. 49 Issue 4 Pg. e12931 (08 2023) ISSN: 1365-2990 [Electronic] England
• PMID: 37565253 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Chemical References

• Protein Phosphatase 2
• tau Proteins
• Betaine
• Folic Acid
• Choline
• Carbon

Topics

• Mice
• Humans
• Animals
• Protein Phosphatase 2 (metabolism)
• tau Proteins (metabolism)
• Betaine
• Tauopathies (pathology)
• Mice, Transgenic
• Alzheimer Disease (metabolism)
• Phosphorylation
• Disease Models, Animal
• Folic Acid
• Choline
• Dietary Supplements
• Carbon