TY - JOUR
T1 - Okadaic acid-induced Tau phosphorylation in rat brain
T2 - Role of NMDA receptor
AU - Kamat, P. K.
AU - Rai, S.
AU - Swarnkar, S.
AU - Shukla, R.
AU - Ali, S.
AU - Najmi, A. K.
AU - Nath, C.
N1 - Funding Information:
Financial support to Pradeep Kumar Kamat is gratefully acknowledged to Council of Scientific and Industrial Research (CSIR) New Delhi, India.
PY - 2013/5/5
Y1 - 2013/5/5
N2 - Okadaic acid (OKA) is a potent inhibitor of protein phosphatases 1/2A (PP2A). Inhibition of PP2A leads to hyperphosphorylation of Tau protein. Hyperphosphorylated Tau protein is present in intraneuronal neurofibrillary tangles a characteristic feature of neuropathology of Alzheimer's disease. Intracerebroventricular (ICV) administration of OKA causes neurotoxicity, which is associated with increased intracellular Ca2+ level, oxidative stress, and mitochondrial dysfunction in the brain areas. The present study explored Tau phosphorylation in OKA-treated rats in relation to memory function, PP2A activity, intracellular Ca2+, glycogen synthase kinase-3β (GSK-3β) and N-methyl-d-aspartate (NMDA) receptor after 13days of OKA (200ng, ICV) administration in rats, memory was found impaired in the water maze test. OKA-induced memory-impaired rats showed increased mRNA and protein expression of Tau, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Calpain and GSK3β in the hippocampus and cerebral cortex. On the other hand, mRNA expression and activity of PP2A was reduced in these brain areas. OKA treatment also, resulted in decrease in mRNA expression of C and N terminals of Tau. Treatment with NMDA antagonist, MK801 (0.05mg/kg, i.p.) for 13days significantly prevented OKA-induced changes in the expression of PP2A, Tau, GSK3β, CaMKII and Calpain. Further, daily administration of anticholinergic drug, donepezil (5mg/kg, p.o.), and the NMDA receptor antagonist, memantine (10mg/kg, p.o.) initiated after OKA administration for 13days significantly attenuated OKA-induced variation in Tau, Tau-C terminal, Tau-N terminal CaMKII, Calpain, PP2A and GSK3β. These results infer that NMDA antagonist MK801 and memantine are effective against OKA-induced neurotoxicity. Therefore, the present study clearly indicates the involvement of NMDA receptor in OKA (ICV)-induced Tau hyperphosphorylation.
AB - Okadaic acid (OKA) is a potent inhibitor of protein phosphatases 1/2A (PP2A). Inhibition of PP2A leads to hyperphosphorylation of Tau protein. Hyperphosphorylated Tau protein is present in intraneuronal neurofibrillary tangles a characteristic feature of neuropathology of Alzheimer's disease. Intracerebroventricular (ICV) administration of OKA causes neurotoxicity, which is associated with increased intracellular Ca2+ level, oxidative stress, and mitochondrial dysfunction in the brain areas. The present study explored Tau phosphorylation in OKA-treated rats in relation to memory function, PP2A activity, intracellular Ca2+, glycogen synthase kinase-3β (GSK-3β) and N-methyl-d-aspartate (NMDA) receptor after 13days of OKA (200ng, ICV) administration in rats, memory was found impaired in the water maze test. OKA-induced memory-impaired rats showed increased mRNA and protein expression of Tau, Ca2+/calmodulin-dependent protein kinase II (CaMKII), Calpain and GSK3β in the hippocampus and cerebral cortex. On the other hand, mRNA expression and activity of PP2A was reduced in these brain areas. OKA treatment also, resulted in decrease in mRNA expression of C and N terminals of Tau. Treatment with NMDA antagonist, MK801 (0.05mg/kg, i.p.) for 13days significantly prevented OKA-induced changes in the expression of PP2A, Tau, GSK3β, CaMKII and Calpain. Further, daily administration of anticholinergic drug, donepezil (5mg/kg, p.o.), and the NMDA receptor antagonist, memantine (10mg/kg, p.o.) initiated after OKA administration for 13days significantly attenuated OKA-induced variation in Tau, Tau-C terminal, Tau-N terminal CaMKII, Calpain, PP2A and GSK3β. These results infer that NMDA antagonist MK801 and memantine are effective against OKA-induced neurotoxicity. Therefore, the present study clearly indicates the involvement of NMDA receptor in OKA (ICV)-induced Tau hyperphosphorylation.
KW - Alzheimer's disease
KW - Donepezil
KW - Memantine
KW - NMDA
KW - Okadaic acid
KW - Tau
UR - http://www.scopus.com/inward/record.url?scp=84876027041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876027041&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2013.01.075
DO - 10.1016/j.neuroscience.2013.01.075
M3 - Article
C2 - 23415789
AN - SCOPUS:84876027041
SN - 0306-4522
VL - 238
SP - 97
EP - 113
JO - Neuroscience
JF - Neuroscience
ER -