Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3…

• UD
  U.S. Department of Defense

  Awards: W81XWH-10-1-0093, W81XWH
• AH
  American Heart Association
• NI
  National Institutes of Health

  Awards: P01 HD29587, P50 AG005131, DA017259, AA020404, W81XWH, P01 ES016738, AG005131