Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease
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The activity of protein phosphatase-2A (PP2A) is compromised and is believed to be a cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. We investigated in AD the role of the two known endogenous PP2A inhibitors, called I1(PP2A) and I2(PP2A), which regulate the intracellular activity of PP2A in mammalian tissues. We found a significant increase in the neocortical levels of I1(PP2A) and I2(PP2A) in AD as compared to control cases by in situ hybridization. The immunohistochemical studies revealed that I2(PP2A) was translocated from neuronal nuclei to cytoplasm in AD. The 39-kd full-length I2(PP2A) was selectively cleaved into an approximately 20-kd fragment in AD brain cytosol. Digestion of the recombinant human I2(PP2A) with AD brain extract showed an increase in the generation of the approximately 20 kd and other fragments of the inhibitor as compared to control brain extract. Double-immunohistochemical studies revealed co-localization of PP2A with PP2A inhibitors in neuronal cytoplasm and co-localization of the inhibitors with abnormally hyperphosphorylated tau. These studies suggest the possible involvement of I1(PP2A) and I2(PP2A) in the abnormal hyperphosphorylation of tau in AD.
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Altered cellular location of endogenous PP2A inhibitors was reported to induce PP2A inactivation in cytoplasm.
“In addition, an altered cellular location of endogenous PP2A inhibitors was reported to induce PP2A inactivation in cytoplasm (Tanimukai et al., 2005).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Tanimukai et al., 2005
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“In addition, an altered cellular location of endogenous PP2A inhibitors was reported to induce PP2A inactivation in cytoplasm (Tanimukai et al., 2005).”
BackgroundProtein-Protein Interactions and Aggregation Inhibitors in Alzheimer’s Disease
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- Authors
- Tanimukai, H., Grundke-Iqbal, I., & Iqbal, K.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 166
- Issue
- 6
- Pages
- 1761-1771
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1602412
- OpenAlex
- W2057058939
- Cited by
- 220
- References
- 53
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 9 · 2022: 12 · 2021: 9 · 2020: 4 · 2019: 11 · 2018: 21 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 14 · 2013: 12 · 2012: 12
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (AG19158)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Alzheimer's disease, protein phosphatase 2A, PP2A inhibitors, tau hyperphosphorylation, neocortex, nuclear-cytoplasmic translocation, proteolytic cleavage
- MeSH terms
- Protein Phosphatase Inhibitory Proteins, Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Immunohistochemistry, Male, Phosphoprotein Phosphatases, Proteins, RNA, Messenger, Blotting, Western, Up-Regulation, tau Proteins, In Situ Hybridization, Protein Transport, Protein Phosphatase 2
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