A Mutant Variant of E2F4 Triggers Multifactorial Therapeutic Effects in 5xFAD Mice

Alzheimer's disease (AD) has a complex etiology, which requires a multifactorial approach for an efficient treatment. We have focused on E2 factor 4 (E2F4), a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brains of Alzheimer's patients and of APP(swe)/PS1(dE9) and 5xFAD transgenic mice. E2F4 contains an evolutionarily conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. In this study, we generated a knock-in mouse strain with neuronal expression of a mouse E2F4 variant lacking this Thr-motif (E2F4DN), which was mated with 5xFAD mice. Here, we show that neuronal expression of E2F4DN in 5xFAD mice potentiates a transcriptional program consistent with the attenuation of the immune response and brain homeostasis. This correlates with reduced microgliosis and astrogliosis, modulation of amyloid-beta peptide proteostasis, and blocking of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. We also show that our finding is significant for AD, since E2F4 is expressed in cortical neurons from Alzheimer patients in association with Thr-specific phosphorylation, as evidenced by an anti-E2F4/anti-phosphoThr proximity ligation assay. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.

Automated summary

Alzheimer's disease (AD) is a complex neurodegenerative disorder that requires a multifaceted approach for effective treatment. In this study, researchers focused on the transcription factor E2 factor 4 (E2F4), which is upregulated in the brains of AD patients and transgenic mice. They generated a mouse strain with neuronal expression of a variant of E2F4 lacking a specific motif (E2F4DN) and found that its expression in 5xFAD mice, a model of AD, attenuated the immune response, improved brain homeostasis, and prevented cognitive impairment and body weight loss. This study suggests that targeting E2F4DN through gene therapy could be a promising approach for treating AD.