Memantine lowers amyloid‐β peptide levels in neuronal cultures and in APP/PS1 transgenic mice

Abstract

Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer's disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Aβ) occurs due to aberrant processing of the full-length Aβ precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Aβ and improves cognition in transgenic mice with high brain levels of Aβ. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Aβ production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 μM), decreased levels of secreted APP and Aβ . Levels of the potentially amylodogenic Aβ 1-42 were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Aβ 1-42 secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Aβ 1-42 , oral dosing of memantine (20 mg/kg/day for 8 days) produced plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ . The ratio of Aβ 1-40 /Aβ 1-42 increased in treated mice, suggesting effects on the γ-secretase complex. Thus, memantine reduces the levels of Aβ peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Aβ in mammalian brains. Memantine's ability to preserve neuronal cells against neurodegeneration, increase metabolic activity, and lower Aβ level has therapeutic implications for neurodegenerative disorders. KeywordsAging; cortex; dementia; lysosome; membrane; tissue culture; memory In Alzheimer's disease (AD), a gradual impairment in short-term memory and cognition results from the dysfunction and death of neurons in the hippocampus, limbic system, and cerebral cortex (Goedert and Spillantini, 2006;Tanzi and Bertram, 2008). AD is characterized by brain * Contributed equally ** Corresponding author: Debomoy K. Lahiri, PhD, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, USA, Tel: (317) 274-2706; Fax: (317) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript depositions of amyloid plaques and neurofibrillary tangles, loss of the synaptophysin protein, and deficits in cholinergic neurotransmission (Giacobini, 2003;Lahiri et al., 2003;Reinhard et al., 2005;Selkoe, 2005). These aberrations are believed to result, in part, from oxidative stress, membrane damage, and the over-production and accumulation of amyloid-β peptide (Aβ), a 39-43 amino acid polypeptide that is a core constituent of amyloid plaques (Dumery et al., 2001;Sambamurti et al., 2006). Two Aβ peptides predominate in brain tissue, one i...

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