Energy-related neurotoxicity at the NMDA receptor: a possible role in Alzheimer's disease and related disorders.
Using rat cerebellar granule cells in primary culture as our model system, we have shown that excitatory amino acids (EAAs) become neurotoxic via the NMDA (N-methyl-D-aspartate) receptor when neuronal energy levels are compromised. Omission of glucose, exclusion of oxygen, or inclusion of inhibitors of oxidative phosphorylation or of Na+/K+-ATPases enables NMDA receptor agonists to express their neurotoxic potential. Both competitive and noncompetitive NMDA receptor antagonists are potent blockers of EAA neurotoxicity, with MK-801 fully effective at 20 nM. We interpret these results as indicating that glucose metabolism, ATP production, and functioning ion pumps are necessary to generate a resting potential sufficient to maintain the voltage-dependent Mg++ block of the NMDA receptor channel; relief of the block enables EAAs to act persistently at the NMDA receptor causing an excessive ion influx which leads to neuronal death by a mechanism not yet understood. These findings are discussed in the context of the potential role for NMDA receptor-mediated neurotoxicity in Alzheimer's disease and related disorders.
Henneberry
R C
RC
Laboratory of Molecular Biology NINDS, NIH, Bethesda, MD 20892.
Novelli
A
A
Vigano
M A
MA
Reilly
J A
JA
Cox
J A
JA
Lysko
P G
PG
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000633:toxicity*; D007473:Ion Channels / Q000378:metabolism; D008274:Magnesium / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D011773:Pyruvates / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*
D005971:Glutamates; D007473:Ion Channels; D011773:Pyruvates; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D008274:Magnesium; D005947:Glucose