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P‐188: Memantine lowers amyloid beta levels in neuronal cells and transgenic mouse models of Alzheimer's disease
Author(s) -
Banerjee Pradeep,
Tanila Heikki,
Wisniewski Thomas,
Gupta Sandeep,
LaFerla Frank,
Lahiri Debomoy K.
Publication year - 2007
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2007.04.151
Subject(s) - memantine , nmda receptor , neuroprotection , genetically modified mouse , pharmacology , neurotoxicity , neuroscience , alzheimer's disease , glutamate receptor , amyloid beta , medicine , transgene , chemistry , receptor , psychology , toxicity , disease , biochemistry , gene
gational product candidate presently in phase III clinical trials for Alzheimer’s disease (AD), is believed to act by binding to soluble A , known to be involved with amyloid deposition in the brain. In addition, we have previously shown that tramiprosate reduces the levels of soluble A 40 and A 42 in the brain and plasma as well as amyloid deposits in an AD transgenic mouse model. Objective(s): The aim of the present study was to assess the ability of tramiprosate to reduce A -mediated toxicity and A levels in vitro using mouse organotypic hippocampal slice cultures (OHC). Methods: In one set of studies, the impact of tramiprosate on cellular mortality was assessed by propidium iodide (PI) staining and by measuring lactate dehydrogenase (LDH) release into the culture media of OHC treated for 72 hours with A 42. In a second set of studies, the effect of tramiprosate on A 40 levels was assessed by ELISA in media conditioned by OHC from either wild-type or transgenic mice (TgCRND8), which express a double mutant human APP cDNA (Swedish, Indiana). Results: Here we demonstrate that concomitant treatment of OHC with tramiprosate and A 42 for 72 hours completely prevented A 42-induced LDH release and cellular mortality in the dentate gyrus, the hippocampal regions CA1 and CA3, and the entorhinal cortex. Treatment of OHC from TgCRND8 mice with 200 M tramiprosate for 3 days significantly reduced the levels of secreted human A 40 by 24%. This effect of tramiprosate was no longer evident following 7 or 10 days of treatment. A similar 3-day treatment of OHC from wild-type mice with tramiprosate demonstrated a more profound effect, resulting in a 40% decrease in the levels of secreted mouse A 40. Conclusions: These data demonstrate that tramiprosate reduces the levels of endogenous and over-expressed A in the conditioned media from mouse OHC, and protects against neurotoxicity resulting from exogenous A administration. Together, these results support a model whereby reduction/elimination of toxic soluble A forms by tramiprosate may contribute to its neuroprotective activity, supporting a potential disease-modifying property of tramiprosate.