Reduced Expression of the PP2A Methylesterase, PME-1, or the PP2A Methyltransferase, LCMT-1, Alters Sensitivity to Beta-Amyloid-Induced Cognitive and Electrophysiological Impairments in Mice

Abstract

Beta-amyloid (Ab) is thought to play a critical role in Alzheimer's disease (AD), and application of soluble oligomeric forms of Ab produces AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic overexpression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to Ab-induced impairments, suggesting that PME-1 inhibition may be an effective approach for preventing or treating these impairments. To explore this possibility, we examined the behavioral and electrophysiological effects of acutely applied synthetic Ab oligomers in male and female mice heterozygous for either a PME-1 KO or an LCMT-1 gene-trap mutation. We found that heterozygous PME-1 KO mice were resistant to Ab-induced impairments in cognition and synaptic plasticity, whereas LCMT-1 gene-trap mice showed increased sensitivity to Ab-induced impairments. The heterozygous PME-1 KO mice produced normal levels of endogenous Ab and exhibited normal electrophysiological responses to picomolar concentrations of Ab, suggesting that reduced PME-1 expression in these animals protects against Ab-induced impairments without impacting normal physiological Ab functions. Together, these data provide additional support for roles for PME-1 and LCMT-1 in regulating sensitivity to Ab-induced impairments, and suggest that inhibition of PME-1 may constitute a viable therapeutic approach for selectively protecting against the pathologic actions of Ab in AD.

Protein phosphatase 2A – structure, function and role in neurodevelopmental disorders

“…PP2A expression and activity are reported to be much reduced in postmortem AD brains samples, whereas the methylation state of PP2A controls the sensitivity and resistance to β-amyloid-induced cognitive and electrophysiological impairments. Consistent with this, multiple in vivo studies have found that inhibiting PP2A produces AD-like tau pathology and cognitive impairment (Gnanaprakash et al, 2021;Nicholls et al, 2016;Staniszewski et al, 2020).…”

Protein phosphatase 2A, complement component 4, and APOE genotype linked to Alzheimer’s disease using a systems biology approach

“…Proteomic analysis of exosomes from human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (P301L or V337M) identified ANP32A, an endogenous PP2A inhibitor, present exclusively in tau-mutant exosomes [48]. Potential clinical implications of our finding on inverse relationships between levels of catalytic subunits of PP2A and the Aβ42 level is indirectly supported by the observation that the heterozygous PME-1 knockout mice which display up-regulated PP2A activity are resistant to Aβ-induced cognitive impairment [49]. Direct activation of PP2A in rat hippocampus by a tricyclic sulfonamide treatment increased PP2A activity, decreased tau phosphorylation and Aβ42/Aβ40 levels in cells, and prevented neuronal synapse impairment [50].…”