Memantine lowers amyloid-β peptide levels in neuronal cultures and in APP/PS1 transgenic mice
✍ Scribed by George M. Alley; Jason A. Bailey; DeMao Chen; Balmiki Ray; Lakshman K. Puli; Heikki Tanila; Pradeep K. Banerjee; Debomoy K. Lahiri
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 387 KB
- Volume
- 88
- Category
- Article
- ISSN
- 0360-4012
No coin nor oath required. For personal study only.
✦ Synopsis
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 Aβ~1–40~. 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 a plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ~1–42~. 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, to increase metabolic activity, and to lower Aβ level has therapeutic implications for neurodegenerative disorders. © 2009 Wiley‐Liss, Inc.