Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks.

Abstract

<p><em>Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy,</em></p><p><em>cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we</em></p><p><em>analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such</em></p><p><em>as Alzheimer’s Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a−/−)</em></p><p><em>mice to evaluate AD progression. Behavioral tests showed that Gadd45a−/− mice presented lower</em></p><p><em>working and spatial memory, pointing out an apparent cognitive impairment compared with WT</em></p><p><em>animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved</em></p><p><em>in its phosphorylation in the hippocampus. Moreover, Gadd45a−/− animals significantly increased the</em></p><p><em>brain’s pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and</em></p><p><em>the dendritic spine length of the neurons were reduced in Gadd45a−/− mice, which could contribute</em></p><p><em>to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the</em></p><p><em>lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that</em></p><p><em>promoting this protein’s expression or function might be a promising therapeutic strategy to slow</em></p><p><em>down AD progression.</em></p>