Dehydroevodiamine attenuates calyculin A-induced tau hyperphosphorylation in rat brain slices.
OBJECTIVE
This study was to investigate the effect of dehydroevodiamine (DHED) on Alzheimer's disease (AD)-like tau hyperphosphorylation induced by calyculin A (CA), an inhibitor of protein phosphatase (PP)-2A and PP-1, and the involvement of PP-2A in metabolically competent rat brain slices.


METHODS
Rat brain slices were pre-incubated at 33 degree centigrade in the presence (10, 100, and 200 micromol/L, respectively) or absence of DHED for 1 h. Then, CA 0.1 micromol/L was added and the slices were treated for another 2 h. Western blotting and/or immunohistochemistry were used to measure the phosphorylation level of tau and PP-2A.


RESULTS
CA treatment could remarkably increase the immunoreactivity of pS262 and decrease the staining of Tau-1, representing tau hyperphosphorylation at Ser262 (pS262) and Ser198/ 199/202 (Tau-1, as the antibody reacts with unphosphorylated tau, therefore, decreased staining represents increased phosphorylation). Pre-incubation of the brain slices with DHED could efficiently attenuate the CA-induced tau hyperphosphorylation at the above AD-related sites. Additionally, DHED also decreased the basal phosphorylation level of tau at Ser396, although CA failed to induce tau hyperphosphorylation at this site. Furthermore, CA treatment induced an increased level of Tyr307-phosphorylated PP-2A, which represents inactivation of the phosphatase, whereas DHED arrested the elevation of the inhibitory modification of PP-2A.


CONCLUSIONS
DHED can attenuate CA-induced tau hyperphosphorylation at multiple AD-related sites in metabolically active rat brain slices. The underlying mechanism may involve a decreased inhibitory phosphorylation of PP-2A at Tyr307.
Fang
Jiang
J
Department of Pathophysiology, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan 430030, China.
Liu
Rong
R
Tian
Qing
Q
Hong
Xiao-ping
XP
Wang
Shao-hui
SH
Cao
Fu-yuan
FY
Pan
Xi-ping
XP
Wang
Jian-zhi
JZ
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D008387:Marine Toxins; D010080:Oxazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D000470:Alkaloids; D008387:Marine Toxins; D010080:Oxazoles; D016875:tau Proteins; D014443:Tyrosine; C028633:dehydroevodiamine; C059041:calyculin A; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2