RT Journal Article
SR Electronic
T1 E2F4 as a single multifactorial target against Alzheimer’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.08.082784
DO 10.1101/2020.05.08.082784
A1 Noelia López-Sánchez
A1 Morgan Ramón-Landreau
A1 Cristina Trujillo
A1 Alberto Garrido-García
A1 José M. Frade
YR 2020
UL http://biorxiv.org/content/early/2020/05/10/2020.05.08.082784.abstract
AB Alzheimer’s disease (AD) has a multifactorial etiology, which requires a single multi-target approach for an efficient treatment. We have focused on E2F4, a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brain of Alzheimer’s patients and of APP/PS1 and 5xFAD transgenic mice. E2F4 contains an evolutionarily-conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. Here we show that neuronal expression in 5xFAD mice of a dominant negative form of E2F4 lacking this Thr-motif (E2F4DN) potentiates a transcriptional program consistent with global brain homeostasis. The latter correlates with attenuation of both microglial immune response and astrogliosis, modulation of Aβ proteostasis, and blockade of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.Competing Interest StatementJ.M. Frade is shareholder (8.96% equity ownership) of Tetraneuron, a biotech company exploiting his patent on the blockade of neuronal tetraploidization by E2F4DN as a therapeutic approach against Alzheimer's disease. N.L.S. received her salary from a R&D contract with Tetraneuron, and currently she works for this biotech company. M.R.L. and A.G.G. works for Tetraneuron.