Biphasic effects of forskolin on tau phosphorylation and spatial memory in rats.
To explore the role of protein kinase A (PKA) in regulating tau phosphorylation and spatial memory, we injected forskolin, an activator of PKA, at different concentrations into the rat brains. We found that forskolin at concentrations up to 80 microM enhanced tau phosphorylation and was associated with prominent spatial memory impairment. Higher concentrations of forskolin, up to 200 microM, were associated with reduced phosphorylation levels of tau and no memory deficits. Forskolin elevated cAMP and activated PKA in a dose-dependent manner. When infused at 200 microM, forskolin also resulted in the activation and overexpression of protein phosphatase-2A (PP-2A) and attenuated the okadaic acid-induced PP-2A inhibition. These data suggest that the upregulation of PKA by forskolin to a certain level may activate PP-2A but that the latter can ameliorate the PKA-induced tau phosphorylation and memory impairment in the rats.
Tian
Qing
Q
Department of Pathophysiology, Key Laboratory of Neurological Disease Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Chin.a tts0001@yahoo.cn
Zhang
Jun-Xia
JX
Zhang
Yao
Y
Wu
Feng
F
Tang
Qian
Q
Wang
Cheng
C
Shi
Zhi-Yong
ZY
Zhang
Jing-Hui
JH
Liu
Sang
S
Wang
Yue
Y
Zhang
Qi
Q
Wang
Jian-Zhi
JZ
D000704:Analysis of Variance; D000818:Animals; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013028:Space Perception / Q000187:drug effects*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; C489131:Mapt protein, rat; D016875:tau Proteins; D005576:Colforsin; D019319:Okadaic Acid; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2