title: Inhibition of extracellular signal-regulated kinase activity improves cognitive function in Tg2576 mice.
abstract: 1. Deposition of β-amyloid (Aβ) peptide is a defining pathological hallmark of Alzheimer's disease (AD) and is involved in memory impairment. Evidence suggests that activation of an extracellular signal-regulated kinase (ERK) pathway is related to Aβ accumulation. Thus, the aim of the present study was to investigate the effects of an ERK inhibitor (U0126) on amyloidogenesis and cognitive function in Tg2576 mice. 2. Tg2576 mice were injected with U0126 (20 mg/kg, i.p.) or vehicle (1% dimethyl sulphoxide in sterile saline) once a day for 7 days and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, immunostaining, western blot analysis, ELISA and enzyme activity assays were used to examine the degree of Aβ deposition in the brains of Tg2576 mice. 3. Our results showed that U0126 attenuated memory impairment and inhibited Aβ deposition in the brains of Tg2576 mice. Further experiments revealed that the inhibition of Aβ deposition by U0126 was due to a reduction in β-secretase and amyloid precursor protein expression in the brains of U0126-treated Tg2576 mice. 4. These results suggest that the ERK pathway is associated with Aβ accumulation and consequent memory dysfunction in Tg2576 mice and that inhibition of the ERK pathway may be an appropriate intervention in the treatment of AD.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Korea.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Choi
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D008569:Memory Disorders / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C509285:Bace2 protein, mouse; D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse