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

George M. Alley, Jason A. Bailey, De Mao Chen, Balmiki Ray, Lakshman K. Puli, Heikki Tanila, Pradeep K. Banerjee, Debomoy K. Lahiri

Research output: Contribution to journalArticle

90 Scopus citations

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-β peptides (Aβ) occurs as a result of 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 Aβ1-40. Levels of the potentially amylodogenic Aβ1-42 were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Aβ1-42 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 Aβ1-42, oral dosing of memantine (20 mg/kg/day for 8 days) produced a plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ1-42. The ratio of Aβ1-40/Aβ1-42 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, to increase metabolic activity, and to lower Aβ level has therapeutic implications for neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)143-154
Number of pages12
JournalJournal of Neuroscience Research
Volume88
Issue number1
DOIs
StatePublished - Jan 2010

Keywords

  • Aging
  • Cortex
  • Dementia
  • Lysosome
  • Membrane
  • Memory
  • Tissue culture

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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    Alley, G. M., Bailey, J. A., Chen, D. M., Ray, B., Puli, L. K., Tanila, H., Banerjee, P. K., & Lahiri, D. K. (2010). Memantine lowers amyloid-β peptide levels in neuronal cultures and in APP/PS1 transgenic mice. Journal of Neuroscience Research, 88(1), 143-154. https://doi.org/10.1002/jnr.22172