Document Type
Article
Publication Title
Journal of Alzheimer’s Disease
Publisher
IOS Press
Publication Date
2-2021
Volume
79
Issue
4
Disciplines
Medical Sciences | Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences
Abstract
Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ).
Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo.
Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice.
Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments.
Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ.
Keywords
Alzheimer’s disease, amyloid-β, cognitive impairment, leucine carboxyl methyltransferase, long-term potentiation, MAPT protein, protein phosphatase 2A, protein phosphatase methylesterase
DOI
10.3233/JAD-200462
Rights
© 2021 – The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Recommended Citation
Gnanaprakash, Madhumathi; Staniszewski, Agnieszka; Zhang, Hong; Pitstick, Rose; Kavanaugh, Michael P.; Arancio, Ottavio; and Nicholls, Russell E., "Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive and Electrophysiological Impairments in Tg2576 APP Transgenic Mice" (2021). Biomedical and Pharmaceutical Sciences Faculty Publications. 73.
https://scholarworks.umt.edu/biopharm_pubs/73