Multiple caspases are involved in beta-amyloid-induced neuronal apoptosis

beta -amyloid peptide (A beta) has been implicated in the pathogenesis of A lzheimer disease and has been reported to induce apoptotic death in cell cu lture. Cysteine proteases, a family of enzymes known as caspases, mediate c ell death in many models of apoptosis. Multiple caspases have been implicat ed in A beta toxicity; these reports are conflicting. We show that treatmen t of cerebellar granule cells (CGC) with A beta (25-35) causes apoptosis as sociated with increased activity of caspases-2, -3 and -6. Selective inhibi tion of each of these three caspases provides significant protection agains t A beta -mediated apoptosis, In contrast, no change in caspase-1 activity was seen after A beta (25-35) application, nor was inhibition of caspase-1 neuroprotective. Similar to CGC, cortical neuronal cultures treated with A beta (25-35) demonstrate increased caspase-3 activity but not caspase-1 act ivity. Furthermore, significant neuroprotection is elicited by selective in hibition of caspase-3 in cortical neurons administered A beta (25-35) where as selective caspase-1 inhibition has no effect. Taken together, these find ings indicate that multiple executioner caspases may be involved in neurona l apoptosis induced by A beta. J. Neurosci. Res. 65:45-53, 2001. (C) 2001 W iley-Liss, Inc.