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

Agnieszka Staniszewski, Hong Zhang, Kesava Asam, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Research output: Contribution to journalArticlepeer-review

Abstract

Beta-amyloid (Aβ) is thought to play a critical role in Alzheimer's disease (AD), and application of soluble oligomeric forms of Aβ produce AD-like impairments in cognition and synaptic plasticity in experimental systems. We found previously that transgenic over expression of the PP2A methylesterase, PME-1, or the PP2A methyltransferase, LCMT-1, altered the sensitivity of mice to AP-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 knockout (KO) or an LCMT-1 gene-trap mutation. We found that heterozygous PME-1 KO mice were resistant to A(3induced impairments in cognition and synaptic plasticity while LCMT-l gene-trap mice showed increased sensitivity to AP-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 AP-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 AP-induced impairments, and suggest that inhibition of PME-1 may constitute a viable therapeutic approach for selectively protecting against the pathological actions of Aβ in AD.

Original languageEnglish
Pages (from-to)4596-4608
Number of pages13
JournalJournal of Neuroscience
Volume40
Issue number23
DOIs
StatePublished - Jun 3 2020

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