title: Oligomeric aggregates of amyloid beta peptide 1-42 activate ERK/MAPK in SH-SY5Y cells via the alpha7 nicotinic receptor.
abstract: The production and aggregation of amyloid beta peptides (Abeta) has been linked to the development and progression of Alzheimer's disease. It is apparent that the various structural forms of Abeta can affect cell signalling pathways and the activity of neurons differently. In this study, we investigated the effects of oligomeric and fibrillar aggregates of Abeta 1-42 (Abeta42) and non-aggregated peptide upon activation of the ERK/MAPK signalling pathway. In SH-SY5Y cells, acute exposure to oligomeric Abeta42 led to phosphorylation of ERK1/2 at concentrations as low as 1 nM and up to 100 nM. These changes were detected as early as 5 min following exposure to 100 nM oligomeric Abeta42, reaching a maximum level after 10 min. Phosphorylation of ERK1/2 subsequently declined to and remained at basal levels after 30 min to 2h of exposure. Fibrillar aggregates of Abeta42 did not significantly induce phosphorylation of ERK1/2 and non-aggregated Abeta42 did not activate the pathway. The effects of oligomeric Abeta42 to increase ERK phosphorylation above basal levels were inhibited by MLA, a specific antagonist of the alpha7 nAChR. U0126, an inhibitor of MEK, the upstream activator of ERK1/2, completely blocked induction of ERK1/2 phosphorylation. Oligomeric aggregates of Abeta42 are the principal structural form of the peptide that activates ERK/MAPK in SH-SY5Y cells and these effects are mediated by the alpha7 nAChR.
authors: Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
authors: Kirk F
authors: KF
authors: Young
authors: Stephen H
authors: SH
authors: Pasternak
authors: R Jane
authors: RJ
authors: Rylett
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D016229:Amyloid beta-Peptides; C579167:Chrna7 protein, human; D004791:Enzyme Inhibitors; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011108:Polymers; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1