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

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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 Aβ25–35 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 Aβ25–35 application, nor was inhibition of caspase‐1 neuroprotective. Similar to CGC, cortical neuronal cultures treated with Aβ25–35 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 Aβ25–35, 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.