JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model
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...
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MDPI AG
2023-03-01
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| Series: | Cells |
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| author | Erica Cecilia Priori Clara Alice Musi Arianna Giani Luca Colnaghi Ivana Milic Andrew Devitt Tiziana Borsello Mariaelena Repici |
| author_facet | Erica Cecilia Priori Clara Alice Musi Arianna Giani Luca Colnaghi Ivana Milic Andrew Devitt Tiziana Borsello Mariaelena Repici |
| author_sort | Erica Cecilia Priori |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T06:47:20Z |
| format | Article |
| id | doaj.art-14ba7e7184d84f70a9c55f98185b539a |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T06:47:20Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-14ba7e7184d84f70a9c55f98185b539a2023-11-17T10:13:30ZengMDPI AGCells2073-44092023-03-0112690410.3390/cells12060904JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse ModelErica Cecilia Priori0Clara Alice Musi1Arianna Giani2Luca Colnaghi3Ivana Milic4Andrew Devitt5Tiziana Borsello6Mariaelena Repici7Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyDivision of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, ItalyCollege of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKCollege of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKDepartment of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, ItalyCollege of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKThe 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.https://www.mdpi.com/2073-4409/12/6/904c-Jun N-terminal kinasesynaptic dysfunctioncognitive declinecell death |
| spellingShingle | Erica Cecilia Priori Clara Alice Musi Arianna Giani Luca Colnaghi Ivana Milic Andrew Devitt Tiziana Borsello Mariaelena Repici JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model Cells c-Jun N-terminal kinase synaptic dysfunction cognitive decline cell death |
| title | JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model |
| title_full | JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model |
| title_fullStr | JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model |
| title_full_unstemmed | JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model |
| title_short | JNK Activation Correlates with Cognitive Impairment and Alteration of the Post-Synaptic Element in the 5xFAD AD Mouse Model |
| title_sort | jnk activation correlates with cognitive impairment and alteration of the post synaptic element in the 5xfad ad mouse model |
| topic | c-Jun N-terminal kinase synaptic dysfunction cognitive decline cell death |
| url | https://www.mdpi.com/2073-4409/12/6/904 |
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