E2F4 as a single multifactorial target against Alzheimer’s disease

Abstract

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 Thrmotif (E2F4DN) potentiates a transcriptional program consistent with global brain homeostasis. The latter correlates with attenuation of both microglial immune response and astrogliosis, modulation of A 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.

E2F4-Based Gene Therapy Mitigates the Phenotype of the Alzheimer's Disease Mouse Model 5xFAD

“…Neuronal expression of murine E2F4DN-myc in transgenic mice leads to slowdown of Aβ accumulation in 5xFAD mice at 3-6 months of age [19]. Consistently, we found that the intravenous administration of AAV-hE24DN in 1.5-monthold h5xFAD mice leads to a time-dependent reduction of Aβ production in the hippocampus (Fig.…”

“…As in our previous study using transgenic mice that express mouse E2F4DN-myc in neurons [19], AAV-hE2F4DN-myc vector administration did not trigger detectable adverse effects. Similar body weight gain was observed during the whole life span in WT mice subjected to systemic delivery of AAV-hE2F4DN-myc when compared with WT mice treated with a control AAV.PHP.B vector expressing EGFP under the control of the hSyn1 promoter control (AAV-EGFP) (Fig.…”

“…Based on previous genetic proof of concept based on a transgenic mouse strain showing neuron-specific expression of a Thr249Ala/Thr251Ala mutant form of mouse E2F4, Myc tagged at its C-terminus (E2F4DN-myc) [19], we hypothesized that human E2F4DN (hE2F4DN), containing Ala mutations in the Thr248/Thr250 motif, could be used as a therapy for AD. To explore methods for delivery of human E2F4DN (hE2F4DN) to the Alzheimer brain, we focused on the adeno-associated vector AAV.PHP.B, a variant of AAV9 with enhanced capacity to cross the blood-brain barrier (BBB) in mice [33].…”

“…The complexity of the AD etiology may explain why, to date, no effective therapies are available for this disease, since the experimental therapies developed so far have mainly been focused on single targets [6] or a combination of specific drugs [18]. We have recently shown that the transcription factor E2 factor 4 (E2F4) could be a multifactorial target for AD [19]. Indeed, E2F4 is a major regulator of most AD-specific gene networks [20], whereas a number of other bioinformatics-based studies further indicate that E2F4 could participate in this disease [21][22][23].…”

“…E2F4 phosphorylation at its conserved Thr261/Thr263 motif in chicken (ortologous of Thr249/Thr251 in mouse and Thr248/Thr250 in human E2F4) can modulate its activity [31], thus resulting in an attractive therapeutic target. In this regard, we have shown that a dominant negative form of E2F4 (E2F4DN), containing Thr > Ala substitutions in this conserved Thr motif, blocks neuronal cell cycle reentry [31] and neuronal tetraploidization (NT) [19,32] and potentiates a transcriptional program consistent with global brain homeostasis, which attenuates neuroinflammation and modulates Aβ proteostasis [19]. This correlates with prevention of cognitive impairment and physiological alterations associated with AD such as body weight loss [19].…”