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It has been shown that β-amyloid (Aβ) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aβ-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aβ-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aβ-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aβ-induced calcium influx, calpain activation and decreased cleavage of p35 to p25. [ABSTRACT FROM AUTHOR]