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.

Beta-amyloid (Aβ) is thought to play a critical role in Alzheimer's disease (AD), and application of soluble oligomeric forms of Aβ 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 Aβ-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 Aβ 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 Aβ-induced impairments in cognition and synaptic plasticity, whereas LCMT-1 gene-trap mice showed increased sensitivity to Aβ-induced impairments. The heterozygous PME-1 KO mice produced normal levels of endogenous Aβ and exhibited normal electrophysiological responses to picomolar concentrations of Aβ, suggesting that reduced PME-1 expression in these animals protects against Aβ-induced impairments without impacting normal physiological Aβ functions. Together, these data provide additional support for roles for PME-1 and LCMT-1 in regulating sensitivity to Aβ-induced impairments, and suggest that inhibition of PME-1 may constitute a viable therapeutic approach for selectively protecting against the pathologic actions of Aβ in AD.SIGNIFICANCE STATEMENT Elevated levels of β-amyloid (Aβ) in the brain are thought to contribute to the cognitive impairments observed in Alzheimer's disease patients. Here we show that genetically reducing endogenous levels of the PP2A methylesterase, PME-1, prevents the cognitive and electrophysiological impairments caused by acute exposure to pathologic concentrations of Aβ without impairing normal physiological Aβ function or endogenous Aβ production. Conversely, reducing endogenous levels of the PP2A methyltransferase, LCMT-1, increases sensitivity to Aβ-induced impairments. These data offer additional insights into the molecular factors that control sensitivity to Aβ-induced impairments, and suggest that inhibiting PME-1 may constitute a viable therapeutic avenue for preventing Aβ-related impairments in Alzheimer's disease.