Fibrillar Abeta (1-42) enhances NMDA receptor sensitivity via the integrin signaling pathway.
The aggregated form of amyloid-beta (Abeta) (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 Ca (2+) measurements. Pretreatment of differentiated SH-SY5Y cells with fibrillar Abeta (1-42) markedly enhanced the intracellular calcium increases caused by NMDA receptor (NMDA-R) stimulation. Function blocking antibody against beta1 integrin depressed the facilitatory effects of Abeta (1-42). Similarly, Abeta (1-42) facilitated NMDA-R driven firing of hippocampal neurons in vivo, and this effect was reduced by neutralizing antibody against beta1 integrins. The positive action of Abeta (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 Abeta (1-42) is recognized by the beta1 subunit containing integrins and may induce a Src kinase dependent NMDA receptor phosphorylation.
Uhász
Gábor J
GJ
Department of Medical Chemistry, University of Szeged, Szeged, H-6720, Hungary.
Barkóczi
Balázs
B
Vass
Gabriella
G
Datki
Zsolt
Z
Hunya
Akos
A
Fülöp
Lívia
L
Budai
Dénes
D
Penke
Botond
B
Szegedi
Viktor
V
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D016023:Integrins / Q000378:metabolism*; D052139:Intracellular Calcium-Sensing Proteins / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016023:Integrins; D052139:Intracellular Calcium-Sensing Proteins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D019061:src-Family Kinases; D002118:Calcium