Candidate Alzheimer’s Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer’s disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer’s disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.

Reduced PTPRD expression differentially alters brain phosphotyrosine phosphoproteomic profiles of 2 and 12 month-old mice

The receptor type protein tyrosine phosphatase PTPRD is implicated in maturation of synapses of expressing neurons, vulnerability to addictions, reward from addictive substances, vulnerability to restless leg syndrome and densities of neurofibrillary pathology in Alzheimer’s disease brains by a variety of evidence. However, PTPRD’s physiological substrates and adaptations to differences in levels of PTPRD expression in brains of young and aging animals have not been explored in depth. We report phosphoproteomic studies of brains of young and aged mice with different levels of PTPRD expression, gene ontology studies of genes identified in this way and validation of several candidate PTPRD substrates with in vitro assays using recombinant PTPRD phosphatase. PTPRD is well positioned to modulate the extent of phosphorylation of phosphotyrosine phosphoprotein substrates, including those involved in synaptic maturation and adaptation.