Sundaresh_2025_Alzheimers.Dement_21_e70947

INTRODUCTION: Oligomeric species of tau are a hallmark of Alzheimer's disease (AD). Given the evidence implicating protein phosphatase 2A (PP2A) in the molecular pathogenesis of tauopathies, we sought to determine whether manipulating the expression of enzymes that regulate PP2A activity, such as leucine carboxyl methyltransferase 1 (LCMT-1) and protein methylesterase 1 (PME-1), would alter pathological responses to oligomeric tau. METHODS: We tested the effect of LCMT-1 and PME-1 overexpression on cognitive and electrophysiological impairments caused by exposure to either recombinant oligomeric human tau or oligomeric tau prepared from mice subjected to blast-induced traumatic brain injury. RESULTS: We found that LCMT-1 overexpression reduced sensitivity while PME-1 overexpression increased sensitivity to tau-induced impairments. Moreover, shockwave exposure increased the propensity of endogenous tau to form toxic oligomers. DISCUSSION: These results suggest that manipulating LCMT-1 or PME-1 activity may represent novel therapeutic approaches for disorders involving exposure to pathogenic forms of oligomeric tau. HIGHLIGHTS: LCMT-1 and PME-1 overexpression alters sensitivity to oligomeric tau-induced impairments. Blast-induced traumatic brain injury increases the propensity of tau to oligomerize. Pathogenic tau-induced cognitive impairments were dependent on its oligomeric form.