Pathological hallmarks of Alzheimer's disease are the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neurodegeneration. The principal component of amyloid plaques is the amyloid-beta peptide (Abeta). Accumulating evidence indicates that Abeta may play a causal role in Alzheimer's disease. In this report, we demonstrate that Abeta deposition and neurotoxicity in human cortical primary neurons are mediated through alpha2beta1 and alphaVbeta1 integrins using specific integrin-blocking antibodies. An aberrant integrin signaling pathway causing the neurotoxicity is mediated through Pyk2. The role of alpha2beta1 and alphaVbeta1 integrins can be extended to another amyloidosis using an amylin in vitro neurotoxicity model. These results indicate that the alpha2beta1 and alphaVbeta1 integrin signaling pathway may be critical components of neurodegeneration in Alzheimer's disease and that integrins may recognize and be activated by a shared structural motif of polymerizing amyloidogenic proteins.