Deletion of <i>Gadd45a</i> Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks

Deletion of <i>Gadd45a</i> Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks

<i>Gadd45</i> 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 <i>Gadd45a</i> activates pathways involved in neurodege...

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Bibliographic Details
Main Authors: Christian Griñán-Ferré, Júlia Jarne-Ferrer, Aina Bellver-Sanchis, Marta Ribalta-Vilella, Emma Barroso, Jesús M. Salvador, Javier Jurado-Aguilar, Xavier Palomer, Manuel Vázquez-Carrera, Mercè Pallàs
Format: Article
Language:English
Published: MDPI AG 2024-02-01
Series:International Journal of Molecular Sciences
Subjects:
cognitive impairment
Alzheimer’s disease
Tau pathology
neuroinflammation
<i>Gadd45a</i>
Online Access:https://www.mdpi.com/1422-0067/25/5/2595
Description
Summary:<i>Gadd45</i> 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 <i>Gadd45a</i> activates pathways involved in neurodegenerative disorders such as Alzheimer’s Disease (AD). This study used wild-type (WT) and <i>Gadd45a</i> knockout <i>(Gadd45a<sup>−/−</sup>)</i> mice to evaluate AD progression. Behavioral tests showed that <i>Gadd45a<sup>−/−</sup></i> 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, <i>Gadd45a<sup>−/−</sup></i> 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 <i>Gadd45a<sup>−/−</sup></i> mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the <i>Gadd45a</i> 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.
ISSN:1661-6596
1422-0067

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