ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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Who cites it
91 citing papers in PubMed, 220 citations in OpenAlex.
- Betaine Attenuates Hyperhomocysteinemia-Induced Cognitive Impairment by Suppressing Oxidative Stress and Activating the PI3K/AKT/GSK-3β Pathway.Antioxidants (Basel, Switzerland) · 2026Article
- Role of Folate Metabolism in Neurodegenerative Diseases: Insight from Experimental and Clinical Studies.Current nutrition reports · 2026Review
- Brain B Vitamin Status and One-Carbon Metabolism Gene Polymorphisms are Associated with Cognitive Impairment in Alzheimer's and Parkinson's Disease.bioRxiv : the preprint server for biology · 2026Article
- The Adiponectin-PP2A Pathway Confers Cognitive Benefits of Physical Exercise Against Chronic Stress-Induced Tau Hyperphosphorylation in the Hippocampus.Aging cell · 2026Article
- Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer's Disease.International journal of molecular sciences · 2025Review
- Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions.Antioxidants (Basel, Switzerland) · 2024Review
- DNA methylation, histone acetylation in the regulation of memory and its modulation during aging.Frontiers in aging · 2024Review
- Methyl donor supplementation reduces phospho-Tau, Fyn and demethylated protein phosphatase 2A levels and mitigates learning and motor deficits in a mouse model of tauopathy.Neuropathology and applied neurobiology · 2023Article
- Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer's disease? From preclinical studies to the clinical trials.Molecular psychiatry · 2023Review
- The Molecular Basis of Wnt/International journal of cell biology · 2023Review
- Ser/Thr phosphatases: One of the key regulators of insulin signaling.Reviews in endocrine & metabolic disorders · 2022Review
- Association of serum s-adenosylmethionine, s-adenosylhomocysteine, and their ratio with the risk of dementia and death in a community.Scientific reports · 2022Article
- Zinc in Regulating Protein Kinases and Phosphatases in Neurodegenerative Diseases.Biomolecules · 2022Review
- Genes Responsible for HBiomolecules · 2022Article
- Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Review
- A Novel Role of PP2A Methylation in the Regulation of Tight Junction Assembly and Integrity.Frontiers in cell and developmental biology · 2022Article
- Alzheimer's disease is an inherent, natural part of human brain aging: an integrated perspective.Free neuropathology · 2022Article
- Tau Acts in Concert With Kinase/Phosphatase Underlying Synaptic Dysfunction.Frontiers in aging neuroscience · 2022Review
- Rho-associated kinases contribute to the regulation of tau phosphorylation and amyloid metabolism during neuronal plasticity.Pharmacological reports : PR · 2021Article
31 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.