PT  - JOURNAL ARTICLE
AU  - Deborah K. Verges
AU  - Jessica L. Restivo
AU  - Whitney D. Goebel
AU  - David M. Holtzman
AU  - John R. Cirrito
TI  - Opposing Synaptic Regulation of Amyloid-β Metabolism by NMDA Receptors <em>In Vivo</em>
AID  - 10.1523/JNEUROSCI.0607-11.2011
DP  - 2011 Aug 03
TA  - The Journal of Neuroscience
PG  - 11328--11337
VI  - 31
IP  - 31
4099  - http://www.jneurosci.org/content/31/31/11328.short
4100  - http://www.jneurosci.org/content/31/31/11328.full
SO  - J. Neurosci.2011 Aug 03; 31
AB  - The concentration of amyloid-β (Aβ) 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 Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ 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 Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levels in vivo. This has implications for understanding normal Aβ metabolism as well as AD pathogenesis.