title: Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction.
abstract: Soluble amyloid-beta (Abeta) 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 Abeta-induced neuronal dysfunction. We investigated the role of neuronal RAGE in Abeta-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 Abeta peptide (Abeta42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, Abeta 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 Abeta, suggesting that neuronal RAGE functions as a signal transducer for Abeta-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by Abeta, 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 Abeta-treated slices. Moreover, Abeta-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that Abeta impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.
authors: Institute of Neuroscience (CNR), Pisa 56100, Italy.
authors: Nicola
authors: N
authors: Origlia
authors: Massimo
authors: M
authors: Righi
authors: Simona
authors: S
authors: Capsoni
authors: Antonino
authors: A
authors: Cattaneo
authors: Fang
authors: F
authors: Fang
authors: David M
authors: DM
authors: Stern
authors: John Xi
authors: JX
authors: Chen
authors: Ann Marie
authors: AM
authors: Schmidt
authors: Ottavio
authors: O
authors: Arancio
authors: Shi Du
authors: SD
authors: Yan
authors: Luciano
authors: L
authors: Domenici
mesh_terms: D000200:Action Potentials / Q000502:physiology / Q000528:radiation effects; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D018728:Entorhinal Cortex / Q000166:cytology; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000528:radiation effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C075222:amyloid beta-protein (1-42); D048051:p38 Mitogen-Activated Protein Kinases