Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production
| Autor: | Sara Sarroca, Coral Sanfeliu, Rubén Corpas, José A. Esteban, Idoia Garcia, Rocío Palenzuela, Carlos G. Dotti, Ander Matheu, Angel R. Nebreda, Sandra Colié |
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| Přispěvatelé: | Marie Curie Memorial Foundation, Ministerio de Economía y Competitividad (España), Institute for Research in Biomedicine (Spain) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Down-Regulation Mice Transgenic Biology Article Mitogen-Activated Protein Kinase 14 Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Alzheimer Disease Neuroplasticity medicine Animals Humans Cognitive Dysfunction Cells Cultured Neuroinflammation Neurons Amyloid beta-Peptides Neuronal Plasticity Multidisciplinary Neurogenesis Long-term potentiation medicine.disease Disease Models Animal 030104 developmental biology Synaptic plasticity Alzheimer Cytokines Alzheimer's disease Neuroscience Gene Deletion 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | DDFV: Repositorio Institucional de la Universidad Francisco de Vitoria Universidad Francisco de Vitoria Digital.CSIC. Repositorio Institucional del CSIC instname Scientific Reports DDFV. Repositorio Institucional de la Universidad Francisco de Vitoria |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep45306 |
| Popis: | Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits. Spanish Ministerio de Economia y Competitividad (MINECO). S.C. was partly supported by the European Union Seventh Framework Programme (FP7/Marie Curie Actions/COFUND). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain) |
| Databáze: | OpenAIRE |
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