title: PP2A methylation controls sensitivity and resistance to β-amyloid-induced cognitive and electrophysiological impairments.
abstract: Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aβ exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Aβ-induced impairments. Neither transgene affected Aβ production or the electrophysiological response to low concentrations of Aβ, suggesting that these manipulations selectively affect the pathological response to elevated Aβ levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Aβ levels in AD patients.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032; erk5@columbia.edu rn95@columbia.edu.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Nicholls
authors.affiliation: The School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2308, Australia;
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Sontag
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032;
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032;
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Staniszewski
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032;
authors.forename: Shijun
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY 10032;
authors.forename: Carla Y
authors.initials: CY
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY 10032;
authors.forename: Michael
authors.initials: M
authors.lastname: Yim
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY 10032;
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Woodruff
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226;
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226;
authors.forename: Brandi
authors.initials: B
authors.lastname: Wasek
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032;
authors.forename: Deqi
authors.initials: D
authors.lastname: Yin
authors.affiliation: Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226;
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: The School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2308, Australia;
authors.forename: Estelle
authors.initials: E
authors.lastname: Sontag
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY 10032; Howard Hughes Medical Institute, Columbia University, New York, NY 10032; Kavli Institute for Brain Science, Columbia University, New York, NY 10032 erk5@columbia.edu rn95@columbia.edu.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032;
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000503:physiopathology*; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D054648:Protein Phosphatase 2 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D054648:Protein Phosphatase 2
keywords: Alzheimer's disease; cognitive impairment; methylation; protein phosphatase 2A; β-amyloid