Evidence of Abeta- and transgene-dependent defects in ERK-CREB signaling in Alzheimer's models.
Extracellular-signal regulated kinase (ERK) signaling is critical for memory and tightly regulated by acute environmental stimuli. In Alzheimer disease transgenic models, active ERK is shown to first be increased, then later reduced, but whether these baseline changes reflect disruptions in ERK signaling is less clear. We investigated the influence of the familial Alzheimer's disease transgene APPsw and beta-amyloid peptide (Abeta) immunoneutralization on cannulation injury-associated (i.c.v. infusion) ERK activation. At both 12 and 22 months of age, the trauma-associated activation of ERK observed in Tg(-) mice was dramatically attenuated in Tg(+). In cortices of 22-month-old non-infused mice, a reduction in ERK activation was observed in Tg(+), relative to Tg(-) mice. Intracerebroventricular (i.c.v.) anti-Abeta infusion significantly increased phosphorylated ERK, its substrate cAMP-response element-binding protein (CREB) and a downstream target, the NMDA receptor subunit. We also demonstrated that Abeta oligomer decreased active ERK and subsequently active CREB in human neuroblastoma cells, which could be prevented by oligomer immunoneutralization. Abeta oligomers also inhibited active ERK and CREB in primary neurons, in addition to reducing the downstream post-synaptic protein NMDA receptor subunit. These effects were reversed by anti-oligomer. Our data strongly support the existence of an APPsw transgene-dependent and Abeta oligomer-mediated defect in regulation of ERK activation.
Ma
Qiu-Lan
QL
Department of Medicine, University of California, Los Angeles, California, USA.
Harris-White
Marni E
ME
Ubeda
Oliver J
OJ
Simmons
Mychica
M
Beech
Walter
W
Lim
Giselle P
GP
Teter
Bruce
B
Frautschy
Sally A
SA
Cole
Greg M
GM
D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D019076:Transgenes / Q000502:physiology*
D016229:Amyloid beta-Peptides; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases