The Journal of Neuroscience
Society for Neuroscience
Medical Sciences | Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences
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.
Alzheimer’s disease; beta-amyloid; cognitive impairment; protein methylation; protein phosphatase 2A; synaptic plasticity
© 2020 the authors
Staniszewski, Agnieszka; Zhang, Hong; Asam, Kesava; Pitstick, Rose; Kavanaugh, Michael P.; Arancio, Ottavio; and Nicholls, Russell E., "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" (2020). Biomedical and Pharmaceutical Sciences Faculty Publications. 72.