| First Author | Staniszewski A | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 23 | Pages | 4596-4608 |
| PubMed ID | 32341098 | Mgi Jnum | J:289529 |
| Mgi Id | MGI:6433701 | Doi | 10.1523/JNEUROSCI.2983-19.2020 |
| Citation | Staniszewski A, et al. (2020) 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. J Neurosci 40(23):4596-4608 |
| abstractText | Beta-amyloid (Abeta) is thought to play a critical role in Alzheimer's disease (AD), and application of soluble oligomeric forms of Abeta 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 Abeta-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 Abeta 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 Abeta-induced impairments in cognition and synaptic plasticity, whereas LCMT-1 gene-trap mice showed increased sensitivity to Abeta-induced impairments. The heterozygous PME-1 KO mice produced normal levels of endogenous Abeta and exhibited normal electrophysiological responses to picomolar concentrations of Abeta, suggesting that reduced PME-1 expression in these animals protects against Abeta-induced impairments without impacting normal physiological Abeta functions. Together, these data provide additional support for roles for PME-1 and LCMT-1 in regulating sensitivity to Abeta-induced impairments, and suggest that inhibition of PME-1 may constitute a viable therapeutic approach for selectively protecting against the pathologic actions of Abeta in AD.SIGNIFICANCE STATEMENT Elevated levels of beta-amyloid (Abeta) 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 Abeta without impairing normal physiological Abeta function or endogenous Abeta production. Conversely, reducing endogenous levels of the PP2A methyltransferase, LCMT-1, increases sensitivity to Abeta-induced impairments. These data offer additional insights into the molecular factors that control sensitivity to Abeta-induced impairments, and suggest that inhibiting PME-1 may constitute a viable therapeutic avenue for preventing Abeta-related impairments in Alzheimer's disease. |
