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The Journal of Neuroscience, March 26, 2008, 28(13):3521-3530; doi:10.1523/JNEUROSCI.0204-08.2008
Development/Plasticity/Repair
Receptor for Advanced Glycation End Product-Dependent Activation of p38 Mitogen-Activated Protein Kinase Contributes to Amyloid-β-Mediated Cortical Synaptic Dysfunction
Nicola Origlia,1 Massimo Righi,2 Simona Capsoni,3 Antonino Cattaneo,4 Fang Fang,5 David M. Stern,7 John Xi Chen,8 Ann Marie Schmidt,5 Ottavio Arancio,6 Shi Du Yan,5,6 andLuciano Domenici1,9 1Institute of Neuroscience (CNR), Pisa 56100, Italy, 2International School for Advanced Studies (SISSA), Trieste 34014, Italy, 3Lay Line Genomics, Rome 00128, Italy, 4European Brain Research Institute, Rome 00143, Italy, 5Department of Surgery and 6Department of Pathology and Taub Institute, Columbia University, New York, New York 10032, 7Dean's Office, University of Cincinnati, Cincinnati, Ohio 45267, 8Harvey Cushing Institutes of Neuroscience, North Shore-Long Island Jewish Health System, New York, New York 11021, and 9Department STB, University of L'Aquila, L'Aquila 67010, Italy
Correspondence should be addressed to either of the following: Luciano Domenici, Institute of Neuroscience (CNR), Via G. Moruzzi 1, 56100, Pisa, Italy, Email: domenici{at}in.cnr.it; or Shi Du Yan, Department of Pathology and Surgery, Taub Institute Columbia University, New York, NY 10032, Email: sdy1{at}columbia.edu
Soluble amyloid-β (Aβ) 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 Aβ-induced neuronal dysfunction. We investigated the role of neuronal RAGE in Aβ-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 Aβ peptide (Aβ42) blocked long-term potentiation (LTP), but did not affect long-term depression, paired-pulse facilitation, or basal synaptic transmission. In contrast, Aβ 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 Aβ, suggesting that neuronal RAGE functions as a signal transducer for Aβ-mediated LTP impairment. To investigate intracellular pathway transducing RAGE activation by Aβ, 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 Aβ-treated slices. Moreover, Aβ-mediated enhancement of p38 MAPK phosphorylation in cortical neurons was reduced by blocking antibodies to RAGE. Together, our results indicate that Aβ impairs LTP in the entorhinal cortex through neuronal RAGE-mediated activation of p38 MAPK.
Key words: amyloid-β; protein; LTP; RAGE; p38 MAPK; entorhinal cortex; Alzheimer's disease
Received June 15, 2007; revised Feb. 19, 2008; accepted Feb. 22, 2008.
Correspondence should be addressed to either of the following: Luciano Domenici, Institute of Neuroscience (CNR), Via G. Moruzzi 1, 56100, Pisa, Italy, Email: domenici{at}in.cnr.it; or Shi Du Yan, Department of Pathology and Surgery, Taub Institute Columbia University, New York, NY 10032, Email: sdy1{at}columbia.edu
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