Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation
Open accessAbstract
Alzheimer's disease (AD) neuropathology is characterized by the accumulation of phosphorylated tau and amyloid-beta peptides derived from the amyloid precursor protein (APP). Elevated blood levels of homocysteine are a significant risk factor for many age-related diseases, including AD. Impaired homocysteine metabolism favors the formation of S-adenosylhomocysteine, leading to inhibition of methyltransferase-dependent reactions. Here, we show that incubation of neuroblastoma cells with S-adenosylhomocysteine results in reduced methylation of protein phosphatase 2A (PP2A), a major brain Ser/Thr phosphatase, most likely by inhibiting PP2A methyltransferase (PPMT). PP2A methylation levels are also decreased after ectopic expression of PP2A methylesterase in Neuro-2a (N2a) cells. Reduced PP2A methylation promotes the downregulation of B alpha-containing holoenzymes, thereby affecting PP2A substrate specificity. It is associated with the accumulation of both phosphorylated tau and APP isoforms and increased secretion of beta-secretase-cleaved APP fragments and amyloid-beta peptides. Conversely, incubation of N2a cells with S-adenosylmethionine and expression of PPMT enhance PP2A methylation. This leads to the accumulation of dephosphorylated tau and APP species and increased secretion of neuroprotective alpha-secretase-cleaved APP fragments. Remarkably, hyperhomocysteinemia induced in wild-type and cystathionine-beta-synthase +/- mice by feeding a high-methionine, low-folate diet is associated with increased brain S-adenosylhomocysteine levels, PPMT downregulation, reduced PP2A methylation levels, and tau and APP phosphorylation. We reported previously that downregulation of neuronal PPMT and PP2A methylation occur in affected brain regions from AD patients. The link between homocysteine, PPMT, PP2A methylation, and key CNS proteins involved in AD pathogenesis provides new mechanistic insights into this disorder.
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PP2A inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease.
“Protein phosphatase 2A (PP2A) inhibition causes hy-perphosphorylation of tau and APP in Alzheimer’s disease (AD).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Sontag et al., 2007
PP2A inactivation is implicated in promoting phosphorylation of APP at T668 and Aβ over-production.
“Furthermore, PP2A inactivation is also implicated in promoting phosphorylation of amyloid precursor protein (APP) at T668 and Aβ over-production (Sontag et al., 2007).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Sontag et al., 2007
PP2A suppression induces APP phosphorylation at T668, leading to enhanced β-secretase processing of APP.
“PP2A suppression also induces APP phosphorylation at the T668 site, leading to enhanced β-secretase processing of APP (Sontag et al., 2007).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Sontag et al., 2007
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“PP2A suppression also induces APP phosphorylation at the T668 site, leading to enhanced β-secretase processing of APP (Sontag et al., 2007).”
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- Authors
- Sontag, E., Nunbhakdi-Craig, V., Sontag, J.-M., Diaz-Arrastia, R., Ogris, E., Dayal, S., Lentz, S. R., Arning, E., & Bottiglieri, T.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Emory University (US)
- Max Perutz Labs (AT)
- University of Iowa (US)
- Baylor University Medical Center (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-03-14
- Volume
- 27
- Issue
- 11
- Pages
- 2751-2759
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672573
- OpenAlex
- W2063618925
- Cited by
- 225
- References
- 61
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 9 · 2022: 10 · 2021: 12 · 2020: 10 · 2019: 11 · 2018: 14 · 2017: 12 · 2016: 10 · 2015: 11 · 2014: 15 · 2013: 14 · 2012: 22
- FWCI
- 12.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG12300, NS-24621)
- National Institute on Aging (P30AG012300, AG 18883, R01AG017861, R56AG018883, AG17861, R01AG018883, AG 12300)
- National Heart, Lung, and Blood Institute (R01HL063943)
- National Institute of Neurological Disorders and Stroke (NS24621, P01NS024621)
- National Center for Complementary and Integrative Health (AT002311, R21AT002311)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- protein phosphatase 2A, homocysteine metabolism, S-adenosylhomocysteine, Alzheimer's disease, tau phosphorylation, amyloid precursor protein, amyloid-beta secretion, APP cleavage, alpha-secretase, beta-secretase, S-adenosylmethionine, cystathionine beta-synthase, hyperhomocysteinemia
- MeSH terms
- Animals, Homocysteine, Methylation, Methyltransferases, Mice, Inbred C57BL, Mice, Transgenic, Phosphoprotein Phosphatases, Amyloid beta-Protein Precursor, tau Proteins, NIH 3T3 Cells, Cell Line, Tumor, Mice, Protein Phosphatase 2
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