In Alzheimer's disease (AD) synapses degenerate and neurons die in brain regions involved in learning and memory processes. Although the cellular and molecular mechanisms underlying the neurodegenerative process in AD are unclear, increasing evidence suggests roles for amyloid beta-peptide (Abeta) and biochemical cascades associated with a form of programmed cell death called apoptosis. Cysteine proteases of the caspase family are activated in neurons undergoing apoptosis and apparently play a major role in the cell death process by cleaving yet-to-be-identified substrates. We now report that caspase activity is increased in brain tissue and neurons from AD patients, and in cultured hippocampal neurons undergoing apoptosis after exposure to amyloid beta-peptide (Abeta). Western blot analyses using antibodies against different subunits of 2-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) types of ionotropic glutamate receptors indicate that AMPA receptor subunits (GluR1, GluR2/3, and GluR4), but not NMDA receptor subunits (NR1 and NR2A), are proteolytically cleaved after exposure of hippocampal neurons to apoptotic insults, including Abeta, and that the caspase inhibitor zVAD-fmk suppresses such cleavage. Western blot analysis of brain tissue from AD patients and age-matched controls revealed evidence for increased proteolysis of AMPA receptor subunits in AD. Our data suggest roles for caspase-mediated cleavage of AMPA receptor subunits in modifying neuronal responsivity to glutamate and in the neurodegenerative process in AD.