A growing body of evidence suggests that the proteolytic cleavage of the microtubule-associated protein tau, the main component of neurofibrillary tangles, might play a role in the molecular mechanisms underlying beta-amyloid (Abeta) -induced neurotoxicity in central neurons. In the present study, we analyzed whether sex hormones could prevent such tau cleavage, and hence, protect rat hippocampal neurons against Abeta toxicity. Our results indicated that estrogen and testosterone prevented caspase-3- and calpain-mediated tau cleavage, respectively. Thus, estrogen decreased the levels of caspase-3-cleaved 50-kDa truncated tau, while testosterone prevented the generation of a calpain-cleaved 17-kDa tau fragment. In addition, our results showed that the decrease in the levels of these tau proteolytic forms was accompanied by an increased cell survival in Abeta-treated neurons. Furthermore, our findings indicated that testosterone was more effective than estrogen in protecting hippocampal neurons against Abeta-induced cell death. Collectively, our data suggest that preventing the decline of estrogen and testosterone associated with normal aging might reduce the susceptibility of central neurons to Abeta-induced toxicity.