期刊
NEUROSCIENCE LETTERS
卷 470, 期 1, 页码 1-5出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2009.11.016
关键词
Amyloid; Alzheimer's drug; beta-Peptide; Dementia; Neuronal cells; Protein processing; sAPP; Secretase; Tissue culture
资金
- Alzheimer's Associations
- National Institutes of Health [AGI 8379, AG18884]
- Intramural Research Program, National Institute on Aging
Memantine, an uncompetitive NMDA receptor antagonist, is a FDA-approved drug used for the treatment of moderate-to-severe Alzheimer's disease (AD). Several studies have documented protective roles of memantine against amyloid beta (A beta) peptide-mediated damage to neurons in both in vitro and in vivo models. Memantine is also effective in reducing amyloid burden in the brain of APP transgenic mice. However, the exact mechanism by which memantine provides protection against A beta-mediated neurodegenerative cascade, including APP metabolism, remains to be elucidated. Herein, we investigated the effect of memantine on levels of the secreted form of A beta precursor protein (APP), secreted A beta and cell viability markers under short/acute conditions. We treated neuronal SK-N-SH cells with 10 mu M memantine and measured levels of secreted total APP (sAPP), APP alpha isoform and A beta((1-40)) in a time dependent manner for up to 24 h. Memantine significantly decreased the levels of the secreted form of sAPP, sAPP alpha and A beta((1-40)) compared to vehicle treated cells. This change started as early as 8 h and continued for up to 24 h of drug treatment. Unlike sAPP, a slight non-significant increase in total intracellular APP level was observed in 24-h treated memantine cells. Taken together, these results suggest a role for memantine in the transport or trafficking of APP molecules away from the site of their proteolytic cleavage by the secretase enzymes. Such a novel property of memantine warrants further study to define its therapeutic utility. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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