Editors' ChoicePharmacology

Better Alzheimer’s Options

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Sci. Signal.  08 Dec 2009:
Vol. 2, Issue 100, pp. ec392
DOI: 10.1126/scisignal.2100ec392

Disruption of synaptic plasticity, specifically long-term potentiation (LTP), by the β-amyloid (Aβ) protein may contribute to the cognitive and memory defects associated with Alzheimer’s disease. Memantine is a low-affinity antagonist of N-methyl-D-aspartate (NMDA) receptors that is approved for treatment of Alzheimer’s dementia, but the doses that prevent Aβ-mediated disruption of LTP can also inhibit LTP on their own. Thus, Hu et al. tested in mice several antagonists that were more selective for NMDA receptors of particular subunit composition to determine whether one would be more effective at blocking Aβ-mediated inhibition of LTP yet would not impair LTP production alone. When coinjected intracerebroventricularly or systemically with an Aβ fragment, antagonists specific for the NR2B (also known as the GluN2B) subunit prevented Aβ-mediated inhibition of LTP at concentrations that did not disrupt LTP when injected alone. Because in vitro data suggest that the Aβ-mediated effect on LTP is indirect, involving release of tumor necrosis factor–α (TNF-α), the authors also showed that inhibition of TNF-α activity also prevented Aβ-mediated inhibition of LTP in vivo and that the NR2B-specific antagonists prevented intracerebrally injected TNF-α from blocking LTP. Finally, the authors showed differential susceptibility to inhibition of LTP by Aβ or TNF-α at basal (not susceptible) or apical (susceptible) dendrites of a specific region of the hippocampus, the stratum oriens.

N.-W. Hu, I. Klyubin, R. Anwy, M. J. Rowan, GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo. Proc. Natl. Acad. Sci. U.S.A. 106, 20504–20509 (2009). [Abstract] [Full Text]