RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

Intracellular amyloid-beta peptide (A beta) has been implicated in neuronal death associated with Alzheimer's disease. Although A beta is predominantly secreted into the extracellular space, mechanisms of A beta transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of A beta from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human A beta subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of A beta and protection from A beta-mediated mitochondrial dysfunction. A beta activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of A beta-RAGE complex. Similar intraneuronal co-localization of A beta and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of A beta from the extracellular to the intracellular space, thereby enhancing A beta cytotoxicity.