Overproduction and accumulation of beta amyloid (Ab) is a pathologic feature of Alzheimer's disease (AD). Entorhinal cortex (EC) is a parahippocampal region involved in learning and memory that is early affected in AD. Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand receptor in the immunoglobulin superfamily that mediates Ab effects on neuronal and non-neuronal cells. To determine the role of RAGE in Ab-induced synaptic dysfunction we recorded extracellular field potentials from cortical layer II/III stimulating the horizontal pathway in layer II-III of in vitro slices containing the EC. We have found that oligomeric Ab peptide (Ab42) in the nanomolar range (200 nM) blocks long-term potentiation (LTP) without affecting long-term depression (LTD), short-term plasticity and basal synaptic transmission. In contrast, bath application of Ab in the micromolar range of concentrations caused a transient depression of basal synaptic transmission and LTD occlusion. Using transgenic (Tg) mice expressing a defective form of RAGE targeted to neurons (DN-RAGE) we showed that neuronal RAGE mediates Ab42 (200nM)-dependent LTP impairment. In contrast, the impairment of synaptic transmission by micromolar Ab was not rescued in slices from Tg DN-RAGE; remarkably, rescue of functional effects was possible in slices from Tg mice expressing defective RAGE targeted to microglia. Our results indicate a prominent role of neuronal and microglial RAGE signalling in EC synaptic dysfunction induced by increasing concentration of Ab.

We suggest that cell-specific activation of RAGE is relevant to development of Ab-dependent impairment of synaptic function.

Grant support: 

AHAF (A2008-335).