Oligomeric aggregates of amyloid β peptide 1–42 activate ERK/MAPK in SH-SY5Y cells via the α7 nicotinic receptor

The production and aggregation of amyloid β peptides (Aβ) has been linked to the development and progression of Alzheimer's disease. It is apparent that the various structural forms of Aβ can affect cell signalling pathways and the activity of neurons differently. In this study, we investigated the effects of oligomeric and fibrillar aggregates of Aβ 1–42 (Aβ42) and non-aggregated peptide upon activation of the ERK/MAPK signalling pathway. In SH-SY5Y cells, acute exposure to oligomeric Aβ42 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 Aβ42, reaching a maximum level after 10 min. Phosphorylation of ERK1/2 subsequently declined to and remained at basal levels after 30 min to 2 h of exposure. Fibrillar aggregates of Aβ42 did not significantly induce phosphorylation of ERK1/2 and non-aggregated Aβ42 did not activate the pathway. The effects of oligomeric Aβ42 to increase ERK phosphorylation above basal levels were inhibited by MLA, a specific antagonist of the α7 nAChR. U0126, an inhibitor of MEK, the upstream activator of ERK1/2, completely blocked induction of ERK1/2 phosphorylation. Oligomeric aggregates of Aβ42 are the principal structural form of the peptide that activates ERK/MAPK in SH-SY5Y cells and these effects are mediated by the α7 nAChR.