title: Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model.
abstract: The Entorhinal cortex (EC) has been implicated in the early stages of Alzheimer's disease (AD). In particular, spreading of neuronal dysfunction within the EC-Hippocampal network has been suggested. We have investigated the time course of EC dysfunction in the AD mouse model carrying human mutation of amyloid precursor protein (mhAPP) expressing human Aβ. We found that in mhAPP mice plasticity impairment is first observed in EC superficial layer and further affected with time. A selective impairment of LTP was observed in layer II horizontal connections of EC slices from 2 month old mhAPP mice, whereas at later stage of neurodegeneration (6 month) basal synaptic transmission and LTD were also affected. Accordingly, early synaptic deficit in the mhAPP mice were associated with a selective impairment in EC-dependent associative memory tasks. The introduction of the dominant-negative form of RAGE lacking RAGE signalling targeted to microglia (DNMSR) in mhAPP mice prevented synaptic and behavioural deficit, reducing the activation of stress related kinases (p38MAPK and JNK). Our results support the involvement of the EC in the development and progression of the synaptic and behavioural deficit during amyloid-dependent neurodegeneration and demonstrate that microglial RAGE activation in presence of Aβ-enriched environment contributes to the EC vulnerability.
authors.affiliation: Neuroscience Institute, Italian National Research Council, Pisa, 56100 Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, Roma, 00143 Roma, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Fontebasso
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, Roma, 00143 Roma, Italy.|Santa Lucia Foundation, Roma 00143, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Middei
authors.affiliation: Neuroscience Institute, Italian National Research Council, Pisa, 56100 Pisa, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Stazi
authors.affiliation: Institute of Cell Biology and Neurobiology, Italian National Research Council, Roma, 00143 Roma, Italy.|Santa Lucia Foundation, Roma 00143, Italy.
authors.forename: Martine
authors.initials: M
authors.lastname: Ammassari-Teule
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
authors.affiliation: Neuroscience Institute, Italian National Research Council, Pisa, 56100 Pisa, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Origlia
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000503:physiopathology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology; D009473:Neuronal Plasticity; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000067759:Receptor for Advanced Glycation End Products; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases