E2F4 IN ALZHEIMER’S DISEASE: A PROMISING THERAPEUTIC TARGET SHAPING SYNAPTIC AND COGNITIVE FUNCTION

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive impairment in cognitive function, particularly memory. Based on our previous findings, which showed that E2F4 is phosphorylated by the stress kinase p38^MAPK at T248/T250 in AD, we investigated the impact of neuronal E2F4 absence and phosphorylation on synaptic function and cognition. To assess that, we used three versions of E2F4: wild type (E2F4WT); dominant negative mutant T248A/T250A (E2F4DN); and constitutively active mutant T248E/T250E (E2F4CA). We demonstrated that E2F4DN acts as a multifactorial therapeutic agent against AD and preserves synaptic long-term potentiation (LTP), the molecular substrate of memory. Moreover, we showed that E2F4 is located in dendritic spines when overexpressed in hippocampal neurons, suggesting a potential role in synaptic regulation. In addition, our in vitro studies proved that both total protein levels and phosphorylation pattern change in all forms of E2F4 after chemically induced LTP (cLTP), indicating that E2F4 participates in synaptic plasticity. Finally, our findings revealed that the loss of neuronal E2F4 in conditional knock out mice alters body weight in females and cognition in both sexes, affecting anxiety-related behaviors (tested with Open Field and Elevated Plus Maze) and memory (tested with Novel Object Location). Together, these findings advance our understanding of E2F4 as a regulator of memory-related mechanisms and underscore the importance of its phosphorylation in promoting synaptic function. Elucidating the role of E2F4 in synaptic function is essential for understanding the mechanisms underlying the therapeutic actions of E2F4DN in AD.