Reciprocal disruption of neuronal signaling and Aβ production mediated by extrasynaptic NMDA receptors: a downward spiral.
It is becoming increasingly clear that aberrant neuronal activity can be the cause and the result of amyloid beta production. Synaptic activation facilitates non-amyloidogenic processing of amyloid precursor protein (APP) and cell survival, primarily through synaptic NMDA receptors (NMDARs) and perhaps specifically those containing GluN2A-subunits. In contrast, extrasynaptic and GluN2B-containing NMDARs promote beta-secretase cleavage of APP into amyloid-beta (Aβ). The opposing nature of these NMDAR populations is reflected in their control over cell survival and death pathways. Subtle changes in glutamate homeostasis may shift the balance between these pathways and could play a role in Alzheimer's disease (AD). Indeed, Aβ production, regional loss of brain connectivity and neurodegeneration correlate with neuronal activity in AD patients. From another perspective, Aβ oligomers (Aβo) alter neuronal signaling through several mechanisms involving NMDARs and intracellular calcium mishandling. While Aβo affect multiple receptors, GluN2B-NMDARs have emerged as primary mediators of altered synaptic plasticity and neurotoxicity. Memantine and its successor, NitroMemantine, are efficient at blocking or reversing the deleterious actions of Aβo largely due to their selectivity for extrasynaptic NMDARs. Recently, Aβo were shown to trigger astrocytic release of glutamate to the extrasynaptic space where it activates NMDARs to promote further Aβ production and synaptic depression. Combined with the reciprocal regulation between neuronal activity and Aβ production, extrasynaptic glutamate release adds to a maladaptive model and ultimately results in synaptotoxicity and neurodegeneration of AD. Extrasynaptic NMDAR antagonists remain as a promising therapeutic avenue by interfering with this cascade.
INSERM, U836, Equipe 12, BP 170, Grenoble, Cedex 9, 38042, France.
Travis
T
Rush
Alain
A
Buisson
D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D020013:Calcium Signaling; D002470:Cell Survival; D015259:Dopamine Agents / Q000494:pharmacology; D018698:Glutamic Acid; D006801:Humans; D008559:Memantine / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism*
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D015259:Dopamine Agents; D018698:Glutamic Acid; D008559:Memantine; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor