Alzheimer's disease (AD) is characterized by the accumulation of protein filaments, namely extracellular amyloid-beta (Abeta) fibrils and intracellular neurofibrillary tangles, which are composed of aggregated hyperphosphorylated tau. Tau hyperphosphorylation is the product of deregulated Ser/Thr kinases such as cdk5 and GSK3beta. In addition, tau hyperphosphorylation also occurs at Tyr residues. To find a link between Abeta and tau phosphorylation, we investigated the effects of short-term Abeta treatments on SHSY-5Y cells. We analyzed phosphorylated tau variants in lipid rafts and the possible role of Tyr18 and Ser396/404 tau phosphorylation in Abeta-induced signaling cascades. After 2 min of Abeta treatment, phospho-Tyr18-tau and its association with rafts increased. Phospho-Ser 396/404-tau became detectable in rafts after 10 min treatment, which temporally correlated with the detection of cdk5 and p35 activator in lipid rafts. To determine the role of cdk5 in tau phosphorylation at Ser396/404 in lipid rafts, we pre-incubated cells with cdk5 inhibitor roscovitine, and observed that the Abeta-induced tau phosphorylation at Ser 396/404 in rafts was abolished as well as cdk5/p35 association with rafts. These data suggest a role for cdk5 in the Abeta-promoted early events involving tau hyperphosphorylation, and their possible implications for AD pathogenesis.