Caspase-3- and calpain-mediated tau cleavage are differentially prevented by estrogen and testosterone in beta-amyloid-treated hippocampal neurons

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 (A beta)-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 A beta toxicity. Our results indicated that estrogen and testosterone prevented caspase-3- and calpainmediated 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 A beta-treated neurons. Furthermore, our findings indicated that testosterone was more effective than estrogen in protecting hippocampal neurons against A beta-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 A beta-induced toxicity. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.