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

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.