okadaic-acid and Folic-Acid-Deficiency

Neurofibrillary tangles (NFTs), which are composed of intracellular filamentous aggregates of hyperphosphorylated tau protein, are one of the pathological hallmarks of Alzheimer's disease (AD). Because tau phosphorylation is regulated by phosphatases, abnormal metabolism of protein phosphatase 2A (PP2A) has been proposed to be a contributing factor to the disease process.. To determine the function of folic acid on tau phosphorylation, an in vitro model of human neuroblastoma cells (SH-SY5Y) were exposed to folic acid (0-40 μmol/L) for 96 h, in the presence or absence of the phosphoesterase inhibitor okadaic acid (OA) (10 nmol/L) for 9 h. The data of western blot showed tau phosphorylation at the Ser396 site in OA-incubated SH-SY5Y cells was inhibited by folic acid in a concentration-dependent manner, with the folic acid concentration of 40 μmol/L providing maximal inhibition. Folic acid can downregulate tau protein phosphorylation by inhibiting the demethylation reactions of PP2A. High folic acid concentrations (20 and 40 μmol/L) increased SAM:SAH ratios and cell viability.. Therefore, we can speculate that folate deficiency may be a cause of PP2A deregulation, which can in turn lead to expression of the abnormal hyperphosphorylated form of tau.

Topics: Alzheimer Disease; Cell Line, Tumor; Cell Survival; Folic Acid; Folic Acid Deficiency; Humans; Methylation; Neuroblastoma; Okadaic Acid; Phosphorylation; Protein Phosphatase 2; tau Proteins

Several recent studies have indicated that increased levels of homocysteine (HC), including that resulting from deficiency in folate, increases tau phosphorylation. Some studies indicate that this is accomplished via HC-dependent activation of NMDA channels and resultant activation of calcium-dependent kinase pathways, while others suggest that the increase in tau phosphorylation is derived via HC-dependent inhibition of methylation of phosphatases and resultant inhibition of phosphatase activity. We demonstrate herein in SH-SY-5Y human neuroblastoma that both of these phenomena contribute to the increase in phospho-tau immunoreactivity following folate deprivation, and that supplementation with S-adenosyl methionine (SAM) prevents both the increase in kinase activity and the decrease in phosphatase activity. These findings demonstrate that the divergent neuropathological consequences of folate deprivation includes multiple pathways that converge upon tau phosphorylation, and further support the notion that dietary supplementation with SAM may reduce or delay neurodegeneration.

Topics: Calcium; Cell Line, Tumor; Drug Interactions; Enzyme Inhibitors; Folic Acid Deficiency; Homocysteine; Humans; N-Methylaspartate; Neuroblastoma; Okadaic Acid; Phosphoric Monoester Hydrolases; Phosphorylation; S-Adenosylmethionine; tau Proteins