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PMID: 15920161 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The American journal of pathology ·Vol. 166 ·No. 6 ·2005-06-00 ·Pages 1761-71

Tanimukai H, Grundke-Iqbal I, Iqbal K

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.

MeSH Terms
Aged Aged, 80 and over Alzheimer Disease/enzymology Blotting, Western Brain/enzymology Female Humans Immunohistochemistry In Situ Hybridization Male Phosphoprotein Phosphatases/antagonists & inhibitors Protein Phosphatase 2 Protein Transport/physiology Proteins/analysis,metabolism RNA, Messenger/analysis Up-Regulation tau Proteins/metabolism
Chemicals
Proteins RNA, Messenger protein phosphatase inhibitor-2 tau Proteins Phosphoprotein Phosphatases Protein Phosphatase 2
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Tanimukai Hitoshi
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314-6399, USA.
Grundke-Iqbal Inge
Iqbal Khalid
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)62486-8
Published
2005-06-00
Pages
1761-71
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1602412
Subset
IM
Grants
NIA NIH HHS · R01 AG019158 · United States
NIA NIH HHS · AG19158 · United States
External Links
PubMed source DOI: 10.1016/S0002-9440(10)62486-8 PMC Full Text View journal details
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