Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats.
Tau hyperphosphorylation leads to formation of paired helical filament/neurofibrillary tangles, the hallmark lesion seen in Alzheimer's disease (AD) brain. An imbalanced regulation in protein kinases and protein phosphatases in the affected neurons is proposed to be a reasonable causative factor to the disease process. To verify the hypothesis, we have injected in the present study calyculin A, a potent and specific inhibitor of protein phosphatase (PP) 2A and PP1, into rat hippocampus bilaterally, thus reproduced an Alzheimer's-like deficiency in dephosphorylation system. It was found that calyculin A-injected rats developed lesions in spatial memory retention in Morris water maze test. At mean time, tau was hyperphosphorylated at Ser396/Ser404 (PHF-1) and Ser-262/Ser-356 (12E8) sites determined both by immunohistochemistry and Western blot. It is implicated that (1) PP2A and PP1 participate in the in vivo regulation of tau phosphorylation, and down-regulation of the two phosphatases will result in tau hyperphosphorylation; (2) hyperphosphorylation of tau at PHF-1 and 12E8 sites might be crucial to affect spatial memory in AD.
Institute of Neuroscience, Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, HUST, 13 Hong Kang Road, Wuhan 430030, PR China.
L
L
Sun
S Y
SY
Liu
X W
XW
Zhou
X C
XC
Wang
R
R
Liu
Q
Q
Wang
J Z
JZ
Wang
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008387:Marine Toxins; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology*; D013550:Swimming / Q000502:physiology; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D000906:Antibodies; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D016875:tau Proteins; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2