| The Abeta peptide is believed to be one of the causative agents of Alzheimer's disease, a pernicious neurodegenerative disorder whose clinical symptoms begin with memory deficits that later encompass dysfunction of higher cognitive areas. Under standing how Abeta affects neuronal function is crucial to developing treatments for Alzheimer's disease.; Electrophysiological and two photon imaging methods were used in organotypic hippocampal slice cultures to study the mechanisms underlying Abeta-induced glutamatergic synaptic depression. First, AP mutants were used to find domains or secondary structures required to depress synaptic transmission. An intact Abeta hydrophobic domain (VFFA), which stabilizes for beta-sheet structure and Abeta oligomerization, appears to be the critical requirement. Abeta-induced synaptic depression partially occludes metabotropic glutamate receptor (mGluR) long-term synaptic depression (LTD) induced by DHPG application and requires p38 MAPK and calcineurin/PP2B activity, two second messengers involved in LTD. AO overexpression results in a decrease in dendritic spine density and a loss of surface GluR2 containing receptors as measured with Super-ecliptic pHluorin (SEP). Using a rectifying GluR2(R607Q) mutant, it was found that Abeta decreases the number of synaptic GluR2 containing receptors. Interestingly, blocking clathrin mediated endocytosis of synaptic GluR2 with GluR2(R607Q;R845A), an AP2-binding deficient mutant of GluR2, blocks Abeta-induced synaptic depression and spine loss. Mimicking constitutive GluR2 endocytosis with a GRIP deficient binding GluR2(R607Q;S880E) mutant also results in synaptic depression of AMPA and NMDA currents and spine loss.; Abeta-induced synaptic depression utilizes normal and reversible cellular processes to induce synaptic depression. Synaptic stabilization of GluR2 receptor is necessary and sufficient to block the structural and electrophysiological effects of Abeta. These studies provide possible mechanisms for how learning deficits occur in Alzheimer's disease and potential therapeutic targets. |
