PP2A methylation controls sensitivity and resistance to β-amyloid-induced cognitive and electrophysiological impairments
Open accessAbstract
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.
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Modulation of PP2A activity in transgenic mouse models supports a causative role for PP2A inhibition in AD pathologies.
“even though modulation of PP2A activity in transgenic mouse models (Nicholls et al., 2016) further supports the causative role for PP2A inhibition in AD pathologies”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Nicholls et al., 2016
PME-1 overexpression caused additional impairments in cognitive/behavioral tests and long-term potentiation in the presence of pathological Aβ concentrations.
“This was accompanied by an added impairment in several cognitive/behavioral tests and long-term potentiation (LTP) in the presence of pathological Aβ concentrations.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
Forebrain LCMT-1 overexpression protected against Aβ-induced impairments despite no detectable changes in PP2A-C methylation.
“Conversely, LCMT-1 overexpression in the forebrain protected against these Aβ-induced impairments, despite any detectable changes in PP2A-C methylation [55].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In LCMT-1 transgenic mice, tau phosphorylation was unchanged while APP Thr668 phosphorylation was decreased.
“In these transgenic mice, no effects on tau phosphorylation were observed, while APP phosphorylation (Thr668) was decreased.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
No impact on motor performance, sensory perception, motivation, or LTP was seen in the absence of Aβ or at very low Aβ concentrations.
“No impact on motor performance, sensory perception, motivation or LTP was seen in the absence of Aβ, or in the presence of very low Aβ concentrations.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
Decreased PP2A-C methylation through forebrain PME-1 overexpression increased tau phosphorylation at Ser396/Ser404, Ser202/Thr205, and Ser262, and APP phosphorylation at Thr668 in the hippocampus.
“Decreased PP2A-C methylation, as observed in an overexpression model of the PP2A methylesterase PME-1 in the entire forebrain, resulted in increased phosphorylation of tau (Ser396/Ser404, Ser202/Thr205, Ser262) and of amyloid precursor protein (APP) at Thr668 in the hippocampus [55].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In these mice, tau phosphorylation is increased.
“-Increased tau and APP phosphorylation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In mice with inducible neuronal expression of FLAG-tagged PME-1, FLAG-PME-1 overexpression reaches 350%.
“-FLAG-PME-1 overexpression: 350% [55]”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In these mice, sensitivity to Aβ-induced cognitive impairments is higher.
“-Higher sensitivity to Aβ-induced cognitive impairments”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In mice with inducible neuronal expression of FLAG-tagged LCMT-1, FLAG-LCMT-1 overexpression reaches 150%.
“-FLAG-LCMT-1 overexpression: 150% [55]”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In these mice, APP phosphorylation is decreased.
“-No effects on tau phosphorylation; decreased APP phosphorylation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In these mice, APP phosphorylation is increased.
“-Increased tau and APP phosphorylation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In these mice, tau phosphorylation is unaffected.
“-No effects on tau phosphorylation; decreased APP phosphorylation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
In these mice, there is protection against Aβ-induced cognitive impairments.
“-Protection against Aβ-induced cognitive impairments”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [55]
Dual-function proteins such as LCMT-1 and PME-1 modulate PP2A activity through methylation and demethylation of the C subunit, depending on the cellular microenvironment.
“Furthermore, dual-function proteins, such as LCMT-1 and PME-1, modulate PP2A activity through methylation [ 199 ] and demethylation [ 94 ] of the C subunit, depending on the cellular microenvironment.”
From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [199]
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Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade
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Self-citationPhysiologic functions of PP2A: Lessons from genetically modified mice
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“However, even though modulation of PP2A activity in transgenic mouse models (Nicholls et al., 2016) further supports the causative role Shentu et al.”
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- Authors
- Nicholls, R. E., Sontag, J.-M., Zhang, H., Staniszewski, A., Yan, S., Kim, C. Y., Yim, M., Woodruff, C. M., Arning, E., Wasek, B., Yin, D., Bottiglieri, T., Sontag, E., Kandel, E. R., & Arancio, O.
- Affiliations
- Columbia University (US)
- Hunter Medical Research Institute (AU)
- Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226;
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-03-07
- Volume
- 113
- Issue
- 12
- Pages
- 3347-3352
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4812727
- OpenAlex
- W2293389683
- Cited by
- 56
- References
- 54
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 3 · 2021: 3 · 2020: 11 · 2019: 2 · 2018: 12 · 2017: 5 · 2016: 3
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (1R01NS092045-01)
- Broitman Foundation (0000)
- DOD | Congressionally Directed Medical Research Programs (W81XWH-12-1-0579)
- Department of Health, Australian Government | National Health and Medical Research Council (APP1002744)
- Hunter Medical Research Institute (G1401436, G1501390)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- protein phosphatase 2A, amyloid-beta, Alzheimer's disease, PME-1, cognitive impairment, transgenic mice, hyperhomocysteinemia
- MeSH terms
- Animals, Behavior, Animal, Cognition Disorders, Methylation, Mice, Transgenic, Amyloid beta-Peptides, Mice, Protein Phosphatase 2
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