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.