Objective: To study the effects of galantamine, approved for Alzheimer's disease (AD) treatment, on the processing of the beta-amyloid precursor protein (APP) and levels of amyloid-beta peptide (Ab) in neuronal cell lines.
Background: One current AD therapeutic strategy is to reduce levels of the toxic Ab (40-42 amino acid) derived from APP (695-770 amino acid). APP is processed by 3 proteases: alpha-, beta-, and gamma-secretases. Alpha-secretase cleaves APP within Ab to the secreted derivative sAPP-alpha, thus precluding Ab formation. In contrast, cleavages of APP by beta- and gamma-secretases result in intact Ab production, leading to amyloid depositions. We studied the effect of galantamine on cellular toxicity, viability, and APP processing pathways in human neuroblastoma (SK-N-SH) cells.
Design/Methods: SK-N-SH cells were treated with galantamine (10 ng to 300 mcg/mL) or vehicle for 24 to 48 hours. Levels of secreted APP and Ab1-40 were measured in the conditioned media samples by Western immunoblotting and sandwich-based ELISA, respectively.
Results: Treatment of SK-N-SH cells with galantamine resulted in no change in Ab1-40 levels in the condition media. However, galantamine treatment exhibited a trend toward an increase in sAPP levels in conditioned media samples without affecting the levels of total intracellular APP. Cell viability and toxicity, determined by MTT and LDH assays, were not affected by galantamine at the concentration range studied for up to 48 hours.
Conclusion: A slight increase in sAPP levels without a concomitant increase in Ab levels by non-toxic dose of galantamine suggest that it may potentially inhibit the amyloidogenic (amyloid formation) pathway.
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