P4-336: Modulation of GSK3beta and MAP kinase pathway via alpha-7 neuronal nicotinic receptors: Potential for disease modification in Alzheimer’s disease

Abstract

Alpha–7 neuronal nicotinic receptors (NNRs) have been implicated in modulating biochemical and neurotransmitter release processes critical to cognitive and neuroprotective processes; however, the underlying mechanisms have been poorly defined. It may be hypothesized that the relatively high degree of calcium permeability of the alpha–7 NNR could trigger biochemical processes, distinct from other NNRs. The objective of this study was to examine, using selective alpha–7 agonists, the role of the two potential pathways – MAP kinase and the PI3K/AKT/GSK3β – implicated in cognitive and neuroprotective effects. Western blot studies were carried out using PC12 cells or primary cortical neurons whereas immunohistochemistry techiques were utilzed to assess phosphorylation changes in brain regions in vivo. Nicotine, choline and alpha–7 NNR agonists such as A–582941 and PNU–282987 increased the phosphorylation of ERK1/2 and/or CREB in a concentration–dependent, antagonist– and allosteric modulator–sensitive manner in vitro in PC12 cells/cortical neurons. The rank order potency (EC50) values of the ligands correlated well with their respective affinities at the alpha–7 NNR. Agonists also activated the PI3K/AKT/GSK3β pathway resulting in increased phosphorylation of GSK3β (ser–9), an inhibitory signal of GSK3β activity. In vivo, the α7 selective agonists such as A–582941 not only activated MAP kinase pathways in the cingulate cortex and dentate gyrus in a dose–dependent manner following acute administration, but also dose–dependently increased GSK3β (ser–9) phosphorylation levels in these brain regions, a process that could lead to attenuation of tau phosphorylation. These studies suggests that selective alpha–7 NNR agonism via enhancing pERK/CREB phosphorylation and inhibiting GSK3 beta activity may be a promising approach for the treatment cognitive deficits associated with various disease states. In particular, selective α7 nAChR activation via P13K/AKT pathway can lead to inactivation of GSK3β (ser–9), a kinase critical to the regulation of tau hyperphosphorylation that is exaggerated in dementias such as Alzheimer's disease.