Opposing Synaptic Regulation of Amyloid-β Metabolism by NMDA Receptors In Vivo

The concentration of amyloid-beta (A beta) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer's disease (AD) pathogenesis. Some types of synaptic activity can regulate A beta levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) A beta levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF A beta levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic A beta generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into A beta. This depression in A beta via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF A beta levels will increase or decrease. NMDA receptor antagonists increase ISF A beta levels, suggesting that basal activity at these receptors normally suppresses A beta levels in vivo. This has implications for understanding normal A beta metabolism as well as AD pathogenesis.