NeuralCipher Research overview
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Abstract Background: Protein phosphatase 2A (PP2A) is considered a potential therapeutic target for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), and catalytic unit methylation of PP2A that relies on methionine and its intermediate S-adenosylmethionine (SAM) regulates most of protein phosphorylation. Manganese overload caused methionine decrease and tau phosphorylation in brain. However, the relationship between PP2Ac and manganese poisoning is not fully understood. In present study, we concentrate on the ameliorative effect of PP2Ac demethylation on cognitive impairment induced by manganese. Methods: Adult male Sprague-Dawley rats (n = 80; 200-250 g) were divided into Subacute (4W) and chronic (16W) exposure groups. Each exposure group consisted of four treatment groups: control (i.p., saline), Mn, methionine, and methionine plus Mn treatment group. N2a cells with different manganese exposure concentrations were cultured with or without methionine, furthermore, ABL127 is used in follow-up studies. Morris water maze, Alamar Blue assay, flow cytometry, Western blot, liquid chromatography, 2,7-dichlorofluorescein diacetate assay were performed to assess spatial memory, cell viability and apoptosis levels，phosphorylated tau and PP2Ac pathway protein expression, SAM content in brain tissue and cells, oixidative stress related markers. Results: Manganese-exposed rats had elevated levels of phosphorylated Tau and PP2Ac demethylation accompanied by abnormal rise of PPME1 expression in cortex and hippocampus as well as restricted SAM in hippocampus and spatial memory function. Up-regulation of PP2Ac demethylation caused by SAM increase after methionine treatment or PPME1 inhibition after ABL127 treatment significantly reduced p-tau, apoptosis and ROS levels, and increased cell viability and GSH levels. In addition, methionine treatment in vivo significantly increased the number of crossings and reduced the escape latency. Conclusion: Methionine and ABL127 treatment can prevent manganese-induced tau hyperphosphorylation and oxidative stress injury, thus improve spatial memory. This improvement is mediated by down-regulation of PP2Ac demethylation. This study confirms that PP2Ac demethylation plays an important role in manganese neurotoxicity and provides a potentially powerful therapeutic strategy for such neurodegenerative diseases.
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