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

Fibrillar amyloid beta (A beta) peptides are major constituents of senile p laques in Alzheimer disease (AD) brain and cause neuronal apoptosis in vitr o. Bar and caspase-3 have been implicated in the pathogenesis of AD and are components of a well-defined molecular pathway of neuronal apoptosis. To d etermine whether A beta-induced neuronal apoptosis involves bar and/or casp ase-3 activation, we examined the effect of A beta on wild-type, bax-defici ent, and caspase-3-deficient telencephalic neurons in vitro. In wild-type c ultures. A beta produced time- and concentration-dependent caspase-3 activa tion, apoptotic nuclear changes. and neuronal death. These neurotoxic effec ts of A beta were not observed in bax-deficient cultures. Caspase-3 deficie ncy, or pharmacological inhibition of caspase activity, prevented caspase-3 activation and blocked the appearance of apoptotic nuclear features but no t A beta-induced neuronal death. Neither calpain inhibition nor microtubule stabilization with Taxol protected telencephalic neurons from A beta-induc ed caspase activation or apoptosis. These results have potential implicatio ns regarding the underlying pathophysiology of AD and towards AD treatment strategies.