α2β1 and αVβ1 integrin signaling pathways mediate amyloid-β-induced neurotoxicity

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-P peptide (A beta). Accumulating evidence indicates that A beta may play a causal role in Alzheimer's disease. In this report, we demonstrate that A beta deposition and neurotoxicity in human cortical primary neurons are mediated through alpha 2 beta 1 and alpha V beta 1 integrins using specific integrin-blocking antibodies. An aberrant integrin signaling pathway causing the neurotoxicity is mediated through Pyk2. The role of alpha 2 beta 1 and alpha V beta 1 integrins can be extended to another amyloidosis using an amylin in vitro neurotoxicity model. These results indicate that the alpha 2 beta 1 and alpha V beta 1 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. (c) 2005 Elsevier Inc. All rights reserved.