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

Soluble amyloid-beta(A beta) 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 beta-induced neuronal dysfunction. We investigated the role of neuronal RAGE in A beta-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 beta peptide (A beta 42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, A beta 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 beta, suggesting that neuronal RAGE functions as a signal transducer for A beta-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by A beta, 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 beta-treated slices. Moreover, A beta-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that A beta impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.