Thursday, 21 August 2003
This presentation is part of : Thursday Poster Sessions

PD-038 Effect of Memantine on Levels of the Amyloid Beta Peptide in Cell Cultures

Debomoy K Lahiri1, George M. Alley1, Cindy Morgan2, Pradeep Banerjee3, and Martin R. Farlow4. (1) Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA, (2) Dept. of Psychiatry, Indiana School of Medicine, Indianapolis, IN, USA, (3) Forest Laboratories, Jersey City, NJ, USA, (4) Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

Objective: Our objective was to study the effects of memantine, a moderate affinity, uncompetitive NMDA receptor antagonist, on the processing of beta-amyloid precursor protein (APP) and levels of amyloid-b peptide (Ab) in neuronal cell lines. One current therapeutic strategy for Alzheimer's disease (AD) is to reduce levels of the toxic Ab, which is derived from APP. APP is processed by three proteases termed a-, b- and g-secretases. The a-secretase cleaves APP within Ab to the secreted derivative sAPPa, precluding Ab formation. In contrast, cleavages of APP by b- and g-secretases result in intact Ab production, leading to amyloid deposition. Since Ab-neurotoxicity is greatly enhanced in the presence of NMDA, we are interested in examining the effects of memantine, which is undergoing clinical trials in the US for the treatment of AD, on APP processing pathways.

Design/Methods: Human neuroblastoma (SK-N-SH) cells were treated with memantine or vehicle for 24-48 hours. The levels of secreted sAPP and Ab1-40 in the conditioned media and the total intracellular APP were measured by western immunoblotting and sandwich-based ELISA assays.

Results: Treatment of human neuroblastoma cells with memantine (25 mM) resulted in a decrease in Ab1-40 levels in the conditioned media (~25% from control). Memantine also exhibited a trend to decrease levels of sAPP in the conditioned media without affecting levels of total intracellular APP. Cell viability and toxicity as determined by MTT and LDH assays were not affected by memantine at the above concentrations for up to 48 hours.

Conclusion: A decrease in Ab1-40 levels without a concomitant increase in cellular APP levels by memantine suggests that it may potentially inhibit the amyloidogenic (amyloid formation) pathway.

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