Premium
Evidence of Aβ‐ and transgene‐dependent defects in ERK‐CREB signaling in Alzheimer’s models
Author(s) -
Ma QiuLan,
HarrisWhite Marni E.,
Ubeda Oliver J.,
Simmons Mychica,
Beech Walter,
Lim Giselle P.,
Teter Bruce,
Frautschy Sally A.,
Cole Greg M.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04869.x
Subject(s) - mapk/erk pathway , creb , transgene , nmda receptor , kinase , endocrinology , medicine , genetically modified mouse , protein kinase a , microbiology and biotechnology , receptor , chemistry , extracellular , biology , biochemistry , transcription factor , gene
Abstract 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 APP sw and β‐amyloid peptide (Aβ) 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‐Aβ 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 Aβ oligomer decreased active ERK and subsequently active CREB in human neuroblastoma cells, which could be prevented by oligomer immunoneutralization. Aβ 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 APP sw transgene‐dependent and Aβ oligomer‐mediated defect in regulation of ERK activation.