Fibrillar Aβ 1-42 Enhances NMDA Receptor Sensitivity via the Integrin Signaling Pathway

Abstract

The aggregated form of amyloid-β (Aβ)_1-42 has been shown to increase N-methyl-D-aspartic acid (NMDA) evoked neuronal activity in vivo. Here we further characterized this phenomenon by investigating the role of integrin activation and downstream Src kinase activity using in vivo electrophysiology and in vitro intracellular Ca²⁺ measurements. Pretreatment of differentiated SH-SY5Y cells with fibrillar Aβ_1-42 markedly enhanced the intracellular calcium increases caused by NMDA receptor (NMDA-R) stimulation. Function blocking antibody against β1 integrin depressed the facilitatory effects of Aβ_1-42. Similarly, Aβ_1-42 facilitated NMDA-R driven firing of hippocampal neurons in vivo, and this effect was reduced by neutralizing antibody against β1 integrins. The positive action of Aβ_1-42 on NMDA-R dependent responses was also depressed by an inhibitor known to block Src kinase. These results support the hypothesis that aggregated Aβ_1-42 is recognized by the β1 subunit containing integrins and may induce a Src kinase dependent NMDA receptor phosphorylation.