JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model

Abstract

The c-Jun N-terminal kinases (JNKs) are a family of proteins that, once activated by stress stimuli, can alter neuronal functions and survival. The JNK cascade plays a crucial role in the post-synaptic neuronal compartment by altering its structural organization and leading, at worst, to an overall impairment of neuronal communication. Increasing evidence suggests that synaptic impairment is the first neurodegenerative event in Alzheimer’s disease (AD). To better elucidate this mechanism, we longitudinally studied 5xFAD mice at three selected time points representative of human AD symptom progression. We tested the mice cognitive performance by using the radial arm water maze (RAWM) in parallel with biochemical evaluations of post-synaptic enriched protein fraction and total cortical parenchyma. We found that 5xFAD mice presented a strong JNK activation at 3.5 months of age in the post-synaptic enriched protein fraction. This JNK activation correlates with a structural alteration of the post-synaptic density area and with memory impairment at this early stage of the disease that progressively declines to cause cell death. These findings pave the way for future studies on JNK as a key player in early neurodegeneration and as an important therapeutic target for the development of new compounds able to tackle synaptic impairment in the early phase of AD pathology.

Publication DOI: https://doi.org/10.3390/cells12060904
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
Funding Information: This research was funded by Ricerca Finalizzata 2016 RF-2016-02361941, MIUR, -PON “Ricerca e Innovazione” PerMedNet id project ARS01_01226-PROGETTI DI RICERCA DI RILEVANTE INTERESSE NAZIONALE Prot. 2017MYJ5TH; European Commission’s Horizon 2020 research a
Additional Information: Copyright © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Uncontrolled Keywords: c-Jun N-terminal kinase,cell death,cognitive decline,synaptic dysfunction,Phosphorylation,Animals,Cognitive Dysfunction/metabolism,Humans,JNK Mitogen-Activated Protein Kinases/metabolism,Mice,Alzheimer Disease/metabolism,MAP Kinase Signaling System,Biochemistry, Genetics and Molecular Biology(all)
Publication ISSN: 2073-4409
Last Modified: 16 May 2024 07:21
Date Deposited: 27 Mar 2023 10:26
Full Text Link:
Related URLs: https://www.mdp ... 3-4409/12/6/904 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-03-15
Published Online Date: 2023-03-15
Accepted Date: 2023-03-15
Authors: Priori, Erica Cecilia
Musi, Clara Alice
Giani, Arianna
Colnaghi, Luca
Milic, Ivana (ORCID Profile 0000-0001-7531-7561)
Devitt, Andrew (ORCID Profile 0000-0002-4651-6761)
Borsello, Tiziana
Repici, Mariaelena (ORCID Profile 0000-0002-9420-528X)

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