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Enhancement of ␣7 nicotinic acetylcholine receptor (nAChR) activity is considered a therapeutic approach for ameliorating cognitive deficits present in Alzheimer's disease and schizophrenia. In this study, we describe the in vitro profile of a novel selective ␣7 nAChR agonist, 5- 120596)], the addition of ABT-107 elicited MLA-sensitive ␣7 nAChRmediated Ca 2ϩ signals in IMR-32 cells and rat cortical cultures and enhanced extracellular signal-regulated kinase phosphorylation in differentiated PC-12 cells. ABT-107 was also effective in protecting rat cortical cultures against glutamate-induced toxicity. In summary, ABT-107 is a selective high affinity ␣7 nAChR agonist suitable for characterizing the roles of this subtype in pharmacological studies.

b-amyloid peptide 1-42 (Ab ) and hyperphosphorylated tau are associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Ab 1-42 can potentiate hyperphosphorylation of tau in cell lines and in transgenic mice, but the underlying mechanism(s) remains unclear. In this study, Ab 1-42 -induced tau phosphorylation was investigated in differentiated PC12 cells. Treatment of cells with Ab 1-42 increased phosphorylation of tau at serine-202 as detected by AT8 antibody. This Ab 1-42 -induced tau phosphorylation paralleled phosphorylation of glycogen synthase kinase-3b (GSK-3b) at tyrosine-216 (GSK-3b-pY216), which was partially inhibited by the GSK-3b inhibitor, CHIR98023. Ab 1-42 -induced tau phosphorylation and increase in GSK-3b-pY216 phosphorylation were also partially attenuated by a7 nicotinic acetylcholine receptor (a7 nAChR) selective ligands including agonist A-582941 and antagonists methyllycaconitine and a-bungarotoxin. The a7 nAChR agonist and the GSK-3b inhibitor had no additive effect. These observations suggest that a7 nAChR modulation can influence Ab 1-42 -induced tau phosphorylation, possibly involving GSK-3b. This study provides evidence of nAChR mechanisms underlying Ab 1-42 toxicity and tau phosphorylation, which, if translated in vivo, could provide additional basis for the utility of a7 nAChR ligands in the treatment of Alzheimer's disease.

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Background and purpose: a7-Nicotinic acetylcholine receptors (a7 nAChRs) play an important role in cognitive function. Positive allosteric modulators (PAMs) amplify effects of a7 nAChR agonist and could provide an approach for treatment of cognitive deficits in neuropsychiatric diseases. PAMs can either predominantly affect the apparent peak current response (type I) or increase both the apparent peak current response and duration of channel opening, due to prolonged desensitization (type II). The delay of receptor desensitization by type II PAMs raises the possibility of Ca 2+ -induced toxicity through prolonged activation of a7 nAChRs. The present study addresses whether type I and II PAMs exhibit different cytotoxicity profiles. Experimental approach: The present studies evaluated cytotoxic effects of type I PAM [N-(4-chlorophenyl)]-a-[(4-chlorophenyl)-aminomethylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and type II PAM 1-[5-chloro-2,4-dimethoxy-phenyl]-3-[5-methyl-isoxazol-3-yl]-urea (PNU-120596), or 4-[5-(4chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulphonamide (A-867744). The studies used cultures of PC12 cells and primary cultures of rat cortical neuronal cells.Key results: Our results showed that neither type I nor type II PAMs had any detrimental effect on cell integrity or cell viability. In particular, type II PAMs did not affect neuron number and neurite outgrowth under conditions when a7 nAChR activity was measured by Ca 2+ influx and extracellular signal-regulated kinases 1 and 2 phosphorylation, following exposure to a7 nAChR agonists. Conclusions and implications:This study demonstrated that both type I and type II a7 nAChR selective PAMs, although exhibiting differential electrophysiological profiles, did not exert cytotoxic effects in cells endogenously expressing a7 nAChRs.