Fibrillar Aβ1-42 Enhances NMDA Receptor Sensitivity via the Integrin Signaling Pathway

Th eaggregate dfor mo famyloid- β(Aβ)1−42 ha sbee nshow nt oincreas eN-methyl-D-asparti caci d(NMDA )evoked neurona lactivit yi nvivo .Her ew efurthe rcharacterize dthi sphenomeno nb yinvestigatin gth erol eo fintegri nactivatio nand downstream Src kinase activity using in vivo electrophysiology and in vitro intracellular Ca 2+ measurements. Pretreatment of differentiated SH-SY5Y cells with fibrillar Aβ1−42 markedly enhanced the intracellular calcium increases caused by NMDA recepto r(NMDA-R )stimulation .Functio nblockin gantibod yagains tβ 1integri ndepresse dth efacilitator yeffect so fAβ1−42. Similarly, Aβ1−42 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 Aβ1−42 on NMDA-R dependent responses was also depressed by an inhibito rknow nt obloc kSr ckinase .Thes eresult ssuppor tth ehypothesi stha taggregate dAβ1−42 i srecognize db yth eβ 1subunit containing integrins and may induce a Src kinase dependent NMDA receptor phosphorylation.