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/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.

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

After decades of unfruitful work, no effective therapies are available for Alzheimer's disease (AD), likely due to its complex etiology that requires a multifactorial therapeutic approach. We have recently shown using transgenic mice that E2 factor 4 (E2F4), a transcription factor that regulates cell quiescence and tissue homeostasis, and controls gene networks affected in AD, represents a good candidate for a multifactorial targeting of AD. Here we show that the expression of a dominant negative form of human E2F4 (hE2F4DN), unable to become phosphorylated in a Thr-conserved motif known to modulate E2F4 activity, is an effective and safe AD multifactorial therapeutic agent.

Neurogranin Expression Is Regulated by Synaptic Activity and Promotes Synaptogenesis in Cultured Hippocampal Neurons.

Neurogranin (Ng) is a calmodulin (CaM)-binding protein that is phosphorylated by protein kinase C (PKC) and is highly enriched in the dendrites and spines of telencephalic neurons. It is proposed to be involved in regulating CaM availability in the post-synaptic environment to modulate the efficiency of excitatory synaptic transmission. There is a close relationship between Ng and cognitive performance; its expression peaks in the forebrain coinciding with maximum synaptogenic activity, and it is reduced in several conditions of impaired cognition.

Activity-dependent translocation of neurogranin to neuronal nuclei.

Long-term changes of synaptic plasticity depend on protein synthesis and transcription. Ng (neurogranin) is a small protein concentrated at dendrites and spines of forebrain neurons, involved in synaptic plasticity through the regulation of CaM (calmodulin)-mediated signalling. Ng presents a central IQ motif that mediates its binding to CaM and PA (phosphatidic acid) and that can be phosphorylated by PKC (protein kinase C).