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MAPK recruitment by beta-amyloid in organotypic hippocampal slice cultures depends on physical state and exposure time.

Bell K.A., O'Riordan K.J., Sweatt J.D., Dineley K.T.

Elevated beta-amyloid is thought to trigger the onset of Alzheimer's disease. Alzheimer's disease is marked by progressive loss of cognitive function, an early symptom of which is episodic memory deficits. Impairment of episodic memory is linked to hippocampal pathology. We investigated the signal transduction consequences of exposure to nanomolar to low micromolar concentrations of aggregate forms of beta-amyloid in the hippocampus. We found that, in addition to activation of ERK MAPK and its downstream target ribosomal S6 kinase in hippocampal slice cultures following acute exposure to oligomeric beta-amyloid(1-42), ERK activation also requires phosphoinositide-3 kinase activity. These effects were contingent on the alpha7 subtype of nicotinic acetylcholine receptor. Hippocampal slice cultures treated acutely with oligomeric beta-amyloid(1-42) did not exhibit JNK MAPK activation; however, chronic exposure to oligomers or high molecular weight aggregates of beta-amyloid(1-42) led to JNK MAPK activation coincident with ERK MAPK down-regulation. In contrast to the effects of acute application of oligomeric beta-amyloid(1-42), nicotine activated ERK MAPK via alpha7 nicotinic acetylcholine receptors utilizing protein kinase A as an intermediate. In conclusion, we found that both the physical state and duration of exposure to beta-amyloid are determinants of MAPK recruitment in hippocampus. We also found that nicotine and beta-amyloid activate ERK MAPK via alpha7 nicotinic acetylcholine receptors but use distinct intermediate kinases. These data indicate the existence of differential coupling of alpha7 to downstream targets depending on the type of ligand that leads to receptor activation.

J Neurochem 91:349-361(2004) [PubMed] [Europe PMC]

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