Multiple caspases are involved in β‐amyloid‐induced neuronal apoptosis

Abstract

β-amyloid peptide (Aβ) has been implicated in the pathogenesis of Alzheimer disease and has been reported to induce apoptotic death in cell culture. Cysteine proteases, a family of enzymes known as caspases, mediate cell death in many models of apoptosis. Multiple caspases have been implicated in Aβ toxicity; these reports are conflicting. We show that treatment of cerebellar granule cells (CGC) with Aβ_25–35 causes apoptosis associated with increased activity of caspases-2, -3 and -6. Selective inhibition of each of these three caspases provides significant protection against Aβ-mediated apoptosis. In contrast, no change in caspase-1 activity was seen after Aβ_25–35 application, nor was inhibition of caspase-1 neuroprotective. Similar to CGC, cortical neuronal cultures treated with Aβ_25–35 demonstrate increased caspase-3 activity but not caspase-1 activity. Furthermore, significant neuroprotection is elicited by selective inhibition of caspase-3 in cortical neurons administered Aβ_25–35, whereas selective caspase-1 inhibition has no effect. Taken together, these findings indicate that multiple executioner caspases may be involved in neuronal apoptosis induced by Aβ. J. Neurosci. Res. 65:45–53, 2001.