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

Erica Cecilia Priori, Clara Alice Musi, Arianna Giani, Luca Colnaghi, Ivana Milic, Andrew Devitt, Tiziana Borsello, Mariaelena Repici

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article number904
Number of pages15
Issue number6
Early online date15 Mar 2023
Publication statusPublished - 15 Mar 2023

Bibliographical note

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/).


  • 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


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