Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer's Disease Hallmarks
Por:
Griñán-Ferré C, Jarne-Ferrer J, Bellver-Sanchis A, Ribalta-Vilella M, Barroso E, Salvador JM, Jurado-Aguilar J, Palomer FX, Vazquez M and Pallàs M
Publicada:
1 mar 2024
Ahead of Print:
23 feb 2024
Resumen:
Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy, cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such as Alzheimer's Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a(-/-)) mice to evaluate AD progression. Behavioral tests showed that Gadd45a(-/-) mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, Gadd45a(-/-) animals significantly increased the brain's pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in Gadd45a(-/-) mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein's expression or function might be a promising therapeutic strategy to slow down AD progression.
Filiaciones:
Griñán-Ferré C:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-National Institute of Health Carlos III, 28029 Madrid, Spain
Jarne-Ferrer J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
Bellver-Sanchis A:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
Ribalta-Vilella M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
Barroso E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Salvador JM:
Department of Immunology and Oncology, National Center for Biotechnology/CSIC, 28049 Madrid, Spain
Jurado-Aguilar J:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Palomer FX:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-National Institute of Health Carlos III, 28029 Madrid, Spain
Pediatric Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Pallàs M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Avda. Joan XXIII 27, 08028 Barcelona, Spain
Institute of Neurosciences of the University of Barcelona, University of Barcelona, 08035 Barcelona, Spain
Spanish Biomedical Research Center in Neurodegenerative Diseases (CIBERNED)-National Institute of Health Carlos III, 28029 Madrid, Spain
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