Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease.
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.
Tanimukai
Hitoshi
H
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314-6399, USA.
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology*; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2; D021381:Protein Transport / Q000502:physiology; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism; D000097847:Protein Phosphatase Inhibitory Proteins
D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D011506:Proteins; D012333:RNA, Messenger; D016875:tau Proteins; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins