Cited by 220Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtein Kinase Regulation and GTPase Signaling

Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease

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Tanimukai, Hitoshi, Grundke-Iqbal, Inge, Iqbal, Khalid·2005·The American Journal of Pathology

Abstract

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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Crossref · 10.1016/s0002-9440(10)62486-8

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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)
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
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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