title: RAGE inhibition in microglia prevents ischemia-dependent synaptic dysfunction in an amyloid-enriched environment.
abstract: Ischemia is known to increase the deleterious effect of β-amyloid (Aβ), contributing to early cognitive impairment in Alzheimer's disease. Here, we investigated whether transient ischemia may function as a trigger for Aβ-dependent synaptic impairment in the entorhinal cortex (EC), acting through specific cellular signaling. We found that synaptic depression induced by oxygen glucose deprivation (OGD) was enhanced in EC slices either in presence of synthetic oligomeric Aβ or in slices from mutant human amyloid precursor protein transgenic mice (mhAPP J20). OGD-induced synaptic depression was ameliorated by functional suppression of RAGE. In particular, overexpression of the dominant-negative form of RAGE targeted to microglia (DNMSR) protects against OGD-induced synaptic impairment in an amyloid-enriched environment, reducing the activation of stress-related kinases (p38MAPK and JNK) and the release of IL-1β. Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by Aβ and triggered by transient ischemia.
authors: Neuroscience Institute, Italian National Research Council, Pisa 56100, Italy, origlia@in.cnr.it luciano.domenici@univaq.it.
authors: Nicola
authors: N
authors: Origlia
authors: Neuroscience Institute, Italian National Research Council, Pisa 56100, Italy, Departments of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67010 L'Aquila, Italy.
authors: Chiara
authors: C
authors: Criscuolo
authors: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032, and.
authors: Ottavio
authors: O
authors: Arancio
authors: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas 66045.
authors: Shirley ShiDu
authors: SS
authors: Yan
authors: Neuroscience Institute, Italian National Research Council, Pisa 56100, Italy, Departments of Applied Clinical Sciences and Biotechnology, University of L'Aquila, 67010 L'Aquila, Italy, origlia@in.cnr.it luciano.domenici@univaq.it.
authors: Luciano
authors: L
authors: Domenici
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: entorhinal cortex; interleukin1-beta; jnk; neuroinflammation; p38mapk; synaptic transmission