Amyloid beta-induced neuronal death is bax-dependent but caspase-independent

Fibrillar amyloid beta (A beta) peptides are major constituents of senile plaques in Alzheimer disease (AD) brain and cause neuronal apoptosis in vitro. Bax and caspase-3 have been implicated in the pathogenesis of AD and are components of a well-defined molecular pathway of neuronal apoptosis. To determine whether A beta-induced neuronal apoptosis involves bax and/or caspase-3 activation, we examined the effect of A beta on wild-type, bax-deficient, and caspase-3-deficient telencephalic neurons in vitro. In wild-type cultures. A beta produced time- and concentration-dependent caspase-3 activation, apoptotic nuclear changes. and neuronal death. These neurotoxic effects of A beta were not observed in bax-deficient cultures. Caspase-3 deficiency, or pharmacological inhibition of caspase activity, prevented caspase-3 activation and blocked the appearance of apoptotic nuclear features but not A beta-induced neuronal death. Neither calpain inhibition nor microtubule stabilization with Taxol protected telencephalic neurons from A beta-induced caspase activation or apoptosis. These results have potential implications regarding the underlying pathophysiology of AD and towards AD treatment strategies.