Okadaic Acid Induces the Rats’ Memory Impairment and Tau Protein Hyperphosphorylation And Intervened by Flavonoids from Stem and Leaf of Scutellaria Baicalensis Georgi

other sites of tau protein. These forms of p-tau protein are found in the AD brain. In addition, the phosphorylation of protein kinases at different sites can alter their kinase activity. For instance, GSK3β activity is inhibited by phosphorylation at serine (Ser) 9, and its activity is enhanced by phosphorylation at tyrosine (Tyr) 216. Hyperphosphorylated tau protein also results from the reduced activity of protein phosphatase (PP2A, PP2B, PP2C, PP1) that indicates a decisive role of PP in tangle formation in AD. Then any strategy that can maintain hyperphosorylation of tau protein can be used to establish an AD-like animal model for studying pathophysiology process and drug screen with AD Okadaic acid (OA), a polyether toxin isolated from marine microalgae, is a selective inhibitor of PP and is neurotoxic. An AD-like animal model was developed by intracerebroventricular injection of OA, which resulted in learning and memory deficits, tau hyperphosphorylation, and NFT accumulation in the brain. This AD-like animal model can be regarded as an accurate simulation of the pathophysiology of AD in vivo SSF, a flavonoid isolated from the stems and leaves of Scutellaria baicalonsis Georgi, has demonstrated beneficial effects towards cognitive improvement in animals with cognitive deficits induced by AlCl3, D-galactose and aggregated Aβ The present study established an AD-like animal model via


Introduction
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. The neuropathology of AD is represented by widespread deposits of neurofibrillary tangles (NFTs) formed by phosphorylated tau (p-tau) protein and of senile plaques (SP) containing amyloid β (Aβ) protein. A series of epidemiological statistical results and the experimental study showed that solely SP cannot result in AD clinical dementia symptoms, while the formation and the number of NFTs is directly related to the occurrence of dementia. NTFs formation is due to excessive phosphorylated tau protein occurred after the formation of the structure of the double helix shape. Actually, tau, a microtubule-binding protein, primarily promotes microtubule stability and contains 2-3 phosphate groups per molecule in the normal brain. However, in the AD brain, tau protein hyperphosphorylated, containing 5-9 phosphate groups per molecule, has a decreased ability to combine with microtubules and dimerize.
Stable tau dimers form tau oligomers, which continue aggregating to form subunits of filaments called protomers. Two protomers wound around each other form a paired helical filament (PHF), and excessive PHF assembly leads to NFTs and eventually AD [1]. An imbalance between tau phosphorylation and dephosphorylation is critical to AD tauopathy. Several protein kinases, including cyclin-dependent kinase 5 (CDK5), cyclic AMPdependent protein kinase (PKA) and glycogen synthase kinase 3β (GSK3β) have been confirmed to phosphorylate tau protein at different sites, such as at serine (Ser) 199, Ser202, Ser262, Ser396, Ser214, Ser404, Thr231 and other sites of tau protein. These forms of p-tau protein are found in the AD brain. In addition, the phosphorylation of protein kinases at different sites can alter their kinase activity. For instance, GSK3β activity is inhibited by phosphorylation at serine (Ser) 9, and its activity is enhanced by phosphorylation at tyrosine (Tyr) 216. Hyperphosphorylated tau protein also results from the reduced activity of protein phosphatase (PP2A, PP2B, PP2C, PP1) that indicates a decisive role of PP in tangle formation in AD. Then any strategy that can maintain hyperphosorylation of tau protein can be used to establish an ADlike animal model for studying pathophysiology process and drug screen with AD [2].
Okadaic acid (OA), a polyether toxin isolated from marine microalgae, is a selective inhibitor of PP and is neurotoxic. An AD-like animal model was developed by intracerebroventricular injection of OA, which resulted in learning and memory deficits, tau hyperphosphorylation, and NFT accumulation in the brain. This ADlike animal model can be regarded as an accurate simulation of the pathophysiology of AD in vivo [3]. SSF, a flavonoid isolated from the stems and leaves of Scutellaria baicalonsis Georgi, has demonstrated beneficial effects towards cognitive improvement in animals with cognitive deficits induced by AlCl3, D-galactose and aggregated Aβ

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the injection of OA into the right lateral cerebral ventricle of rats.
We investigated the effects of SSF on memory impairment, neuron injury, NFT deposition, tau protein phosphorylation at Ser199, Ser202, Ser214, Ser262, Ser396, Ser404 and Thr231 in the brain and examined the effects of SSF on the regulatory mechanisms of CDK5, PKA, GSK3β and PP.
The current studies demonstrated that SSF is improved memory deficits and neuroprotective against OA primary from lowering the hyperphosphorylation of tau protein and regulative balance of protein kinases and protein phosphatase activites and then inhibiting PHF increase. These findings, coupled with our previous studies, indicate that the action of SSF is based on multiple targets, which may be predicted beneficial effects for the treatment of AD.