Reduced expression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, alter sensitivity to beta-amyloid induced cognitive and electrophysiological impairments in mice.

Beta-amyloid (A beta) is thought to play a critical role in Alzheimer's disease (A beta), and application of soluble oligomeric forms of A beta 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 A beta-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 A beta 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 A beta-induced impairments in cognition and synaptic plasticity, whereas LCMT-1 gene-trap mice showed increased sensitivity to A beta-induced impairments. The heterozygous PME-1 KO mice produced normal levels of endogenous A beta and exhibited normal electrophysiological responses to picomolar concentrations of A beta, suggesting that reduced PME-1 expression in these animals protects against A beta-induced impairments without impacting normal physiological A beta functions. Together, these data provide additional support for roles for PME-1 and LCMT-1 in regulating sensitivity to A beta-induced impairments, and suggest that inhibition of PME-1 may constitute a viable therapeutic approach for selectively protecting against the pathologic actions of A beta in AD.