An okadaic acid induced Alzheimer’s model and the neuroprotective effects of estrogen
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Alzheimer’s disease (AD) is a neurodegenerative disease that causes progressive cognitive and behavior deterioration in the elderly over age 65, although the lessprevalent early-onset AD can occur much earlier. AD is the most common cause of dementia, accounting for 50 to 70 percent of all dementia cases. Affected brains of AD are characterized by the presence of senile plaques (SP), neurofibrillary tangles (NFTs) and the loss of cholinergic neurons in the basal forebrain. To date, not only is there no cure for AD, but also the cause and the factors that underlie the progression of AD are not well known. It is critical to develop useful animal models to study the pathology of AD for preclinical testing of drugs. It is well known that very few species develop the behavioral, cognitive and neuropathological symptoms of AD spontaneously. To date, no ideal animal AD tau models have been described. Most of the commonly used tau transgenic models are associated with the development of motor impairments, which significantly limit the use of these models in behavioral tests. In the present study, in an attempt to characterize a new experimental in vivo AD model, okadaic acid (OA), a protein phosphatase inhibitor, was microinfused unilaterally, via an osmotic pump, into the dorsal hippocampus area of ovariectomized female adult rat. After 14 days of OA infusion, rats were subjected to behavior tasks, including spatial learning and memory learning (as assessed by Morris Water Maze) and motor function (by Rotarod). Then the rat brain was subject to Bielschowsky’s silver staining and immunohistochemistry for testing tau pathology. Meanwhile, right after the OA infusion, the model was subjected to testing the levels of phosphorylated tau, tau protein phosphatases and certain tau kinases without behavioral tests. Our data showed that the unilateral microinfusion of OA into the dorsal hippocampus could contribute to a cognitive deficiency as well as NFTs-like pathological changes evidenced by the significant increase of tau hyperphosphorylation. Further, our data revealed that cdk5 may be involved in OA induced tau hyperphosphorylation. Our data also showed that the unilateral microinfusion of OA into dorsal hippocampus induced oxidative stress in both cortex and hippocampus. Epidemiological studies showed that AD is three times more prevalent in women than men and estrogen protects against AD. To investigate the effect of estrogen on tau phosphorylation, SH-SY5Y cell line was treated with OA to induce tau phosphorylation and the neuroprotective effects of estrogen were observed by co-treatment with estrogen. We found OA induced in vitro tau hyperphosphorylation, which was prevented by estrogen in a dose dependent manner. This preventive effect could be partially blocked by ICI 182,780, an estrogen receptor (ER) antagonist. Meanwhile, an OA induced ugregulation of cdk5 and inactive GSK3β (p-Ser 9) levels were also observed. Estrogen was able to block this effect but counteracted by ICI 182,780. Our results suggest that cdk5 may be involved in OA induced tau hyperphosphorylation and estrogen can prevent the tau hyperphosphorylation via re-establishing the balance between tau kinases and phosphatases. This effect may be mediated by an ER.