Modulación de la respuesta inmune por la expresión neuronal de E2F4DN en el cerebro del modelo murino de Alzheimer 5xFAD

Résumé

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex etiology, which requires a multifactorial approach for an efficient treatment. Transcription factor E2F4, which regulates cellular quiescence and tissue homeostasis, has been shown to control gene networks affected in AD. Furthermore, E2F4 is upregulated in the brains of Alzheimer's patients and in the murine model of Alzheimer's disease 5xFAD. E2F4 contains two evolutionarily conserved Thr-motifs that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. In this study, a knock-in mouse strain was generated, with neuronal expression of a mouse E2F4 variant lacking these Thr residues (E2F4DN). These mice, together with their EGFP knock-in controls, were bred with 5xFAD mice to analyze the effects of the expression of E2F4DN in such a murine model of Alzheimer's disease. Results in this work show that neuronal expression of E2F4DN in 5xFAD mice mitigates the immune response. Reduced microgliosis and astrogliosis are correlated with this effect, as well as modulation of amyloid-β peptide (Aβ) proteostasis. In addition, the expression of E2F4DN in neurons has been observed to lead to soluble factor-mediated communication between these cells and microglia. A gene therapy based on E2F4DN could be a good multifactorial approach against AD. Therefore, the expression of a dominant negative form of human E2F4 (hE2F4DN) in neurons of homozygous 5xFAD (h5xFAD) mice, due to the systemic administration of an AAV.PHP.B-hSyn1.hE2F4DN vector, has been under study. As in the 5xFAD/E2F4DN transgenic mice, the expression of hE2F4DN followed by the intravenous administration of the vector in h5xFAD mice led to the attenuation of reactive astrocytosis and microgliosis, and reduced βA accumulation in the hippocampus. After decades of unsuccessful work, no effective therapies are available for AD, probably due to its complex etiology requiring a multifactorial therapeutic approach. These results show that E2F4DNbased gene therapy is a promising therapeutic approach against AD