Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-?-mediated cortical synaptic dysfunction

Soluble amyloid-? (A?) peptide is likely to play a key role during early stages of Alzheimer's disease (AD) by perturbing synaptic function and cognitive processes. Receptor for advanced glycation end products (RAGE) has been identified as a receptor involved in A?-induced neuronal dysfunction. We investigated the role of neuronal RAGE in A?-induced synaptic dysfunction in the entorhinal cortex, an area of the brain important in memory processes that is affected early in AD. We found that soluble oligomeric A? peptide (A?42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, A? did not inhibit LTP in slices from RAGE-null mutant mice or in slices from wild-type mice treated with anti-RAGE IgG. Similarly, transgenic mice expressing a dominant-negative form of RAGE targeted to neurons showed normal LTP in the presence of A?, suggesting that neuronal RAGE functions as a signal transducer for A?-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by A?, we used inhibitors of stress activated kinases. We found that inhibiting p38 mitogen-activated protein kinase (p38 MAPK), but not blocking c-Jun N-terminal kinase activation, was capable of maintaining LTP in A?-treated slices. Moreover, A?-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that A? impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK. Copyright © 2008 Society for Neuroscience.