Folic Acid Reduces Tau Phosphorylation by Regulating PP2A Methylation in Streptozotocin-Induced Diabetic Mice.

Mengyue Li,Guowei Huang,Miaoyan Zheng,Yuxia Gao,Huan Liu,Chen Zou

doi:10.3390/ijms18040861

Abstract

High incidence rate of Alzheimer’s disease (AD) is observed in patients with type 2 diabetes. Aggregated β-amyloid (Aβ) and hyperphosphorylated tau are the hallmarks of AD. Hyperphosphorylated tau has been detected in diabetic animals as well as in diabetic patients. Folates mediate the transfer of one carbon unit, required in various biochemical reactions. The effect of folate on tau phosphorylation in diabetic models still remains unknown. In this study, we investigated the effect and mechanism of folic acid on hyperphosphorylation of tau in streptozotocin (STZ)-induced diabetic mice. Diabetic mice induced by STZ, at the age of 10 weeks, were administered with three levels of folic acid: folic acid-deficient diet, diet with normal folic acid content, and 120 μg/kg folic acid diet for 8 weeks. Levels of serum folate and blood glucose were monitored. Tau phosphorylation, protein phosphatase 2A (PP2A) methylation, and Glycogen synthase kinase 3β (GSK-3β) phosphorylation were detected using Western blot. The S-adenosyl methionine:S-adenosyl homocysteine ratio (SAM:SAH) in brain tissues was also determined. DNA methyltransferase (DNMT) mRNA expression levels were detected using real-time PCR. Folic acid reduced tau hyperphosphorylation at Ser396 in the brain of diabetes mellitus (DM) mice. In addition, PP2A methylation and DNMT1 mRNA expression were significantly increased in DM mice post folic acid treatment. GSK-3β phosphorylation was not regulated by folic acid administration. Folic acid can reduce tau phosphorylation by regulating PP2A methylation in diabetic mice. These results support that folic acid can serve as a multitarget neuronal therapeutic agent for treating diabetes-associated cognitive dysfunction.

Highlights

Epidemiological studies show high incidence rate of Alzheimer’s disease (AD) in patients with type 2 diabetes [1,2,3]
A number of cross-sectional and longitudinal studies have examined the association between type II diabetes mellitus (DM) and cognitive impairment [4,5], mild cognitive impairment (MCI), and dementia [6]
Amyloid-β (Aβ), a peptide derived from the amyloid protein precursor (APP), and hyperphosphorylated tau are the major components of senile plaques and neurofibrillary tangles (NFTs) respectively [7]

Summary

Introduction

Epidemiological studies show high incidence rate of Alzheimer’s disease (AD) in patients with type 2 diabetes [1,2,3]. Amyloid-β (Aβ), a peptide derived from the amyloid protein precursor (APP), and hyperphosphorylated tau are the major components of senile plaques and NFTs respectively [7]. Tau is a neuronal cytoskeletal protein responsible for microtubulin polymerization and stabilization. It suggests that tau, a microtubule associated protein, plays a key role in the pathogenesis of AD as Aβ. Hyperphosphorylated tau fails to bind and stabilize microtubules, resulting in destabilization of the cytoskeleton and perturbation of axonal transport [8].

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Results