Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model

Chiara Criscuolo, Veronica Fontebasso, Silvia Middei, Martina Stazi, Martine Ammassari-Teule, Shirley Shidu Yan, Nicola Origlia

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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.

Original languageEnglish
Article number42370
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - Feb 13 2017

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Entorhinal Cortex
Alzheimer Disease
Amyloid beta-Protein Precursor
Mutation
MAP Kinase Kinase 4
Inhibition (Psychology)
Microglia
Amyloid
Synaptic Transmission

ASJC Scopus subject areas

  • General

Cite this

Criscuolo, C., Fontebasso, V., Middei, S., Stazi, M., Ammassari-Teule, M., Yan, S. S., & Origlia, N. (2017). Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model. Scientific Reports, 7, [42370]. https://doi.org/10.1038/srep42370

Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model. / Criscuolo, Chiara; Fontebasso, Veronica; Middei, Silvia; Stazi, Martina; Ammassari-Teule, Martine; Yan, Shirley Shidu; Origlia, Nicola.

In: Scientific Reports, Vol. 7, 42370, 13.02.2017.

Research output: Contribution to journalArticle

Criscuolo, C, Fontebasso, V, Middei, S, Stazi, M, Ammassari-Teule, M, Yan, SS & Origlia, N 2017, 'Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model', Scientific Reports, vol. 7, 42370. https://doi.org/10.1038/srep42370
Criscuolo, Chiara ; Fontebasso, Veronica ; Middei, Silvia ; Stazi, Martina ; Ammassari-Teule, Martine ; Yan, Shirley Shidu ; Origlia, Nicola. / Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model. In: Scientific Reports. 2017 ; Vol. 7.
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