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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\u2019s 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.<\/jats:p>","DOI":"10.3390\/cells12060904","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T03:50:45Z","timestamp":1678938645000},"page":"904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model"],"prefix":"10.3390","volume":"12","author":[{"given":"Erica Cecilia","family":"Priori","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy"},{"name":"Mario Negri Institute for Pharmacolgical Research\u2014IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Alice","family":"Musi","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy"},{"name":"Mario Negri Institute for Pharmacolgical Research\u2014IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Giani","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy"},{"name":"Mario Negri Institute for Pharmacolgical Research\u2014IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9699-5318","authenticated-orcid":false,"given":"Luca","family":"Colnaghi","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7531-7561","authenticated-orcid":false,"given":"Ivana","family":"Milic","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Devitt","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Borsello","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, Universit\u00e0 degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy"},{"name":"Mario Negri Institute for Pharmacolgical Research\u2014IRCCS, Via Mario Negri 2, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariaelena","family":"Repici","sequence":"additional","affiliation":[{"name":"College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105090","DOI":"10.1016\/j.phrs.2020.105090","article-title":"Map Kinase Signaling as Therapeutic Target for Neurodegeneration","volume":"160","author":"Ahmed","year":"2020","journal-title":"Pharmacol. 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