Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8

The Alzheimer disease-associated beta-amyioid peptide has been shown to ind uce apoptotic neuronal death. In the present study, we test the hypothesis that the apoptotic pathway activated by beta-amyloid is similar to the path way activated by the Fas/TNFR family of death receptors, which requires cas pase-8 activity and adaptor proteins such as FADD. We demonstrate that the selective caspase-8 inhibitor IETD-fmk blocks neuronal death induced by bet a-amyioid. Furthermore, using viral-mediated gene delivery, we show that ne urons expressing dominant-negative FADD are protected from apoptosis induce d by beta-amyloid. Together these results indicate that the apoptotic pathw ay activated by beta-amyloid requires both caspase-8 activity and FADD. The se findings further support the hypothesis that beta-amylold might initiate apoptosis by cross-linking death receptors of the Fas/TNFR family. (C) 199 9 Academic Press.