HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Abstract

R e s e a R c h a R t i c l e3

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…Finally, the inhibition of HDAC6 may facilitate the degradation of misfolded proteins, such as Aβ and pTau (Sung et al, 2012;Yu et al, 2013;Zhang et al, 2014). Although different studies have demonstrated that HDACi or PDE5i improved cognitive deficits in animal models of AD, their role on amyloid pathology is controversial (Benito et al, 2015;Cuadrado-Tejedor et al, 2011b;Garcia-Barroso et al, 2013;Puzzo et al, 2009;Qing et al, 2008;Ricobaraza et al, 2009;Rumbaugh et al, 2015;Zhang and Schluesener, 2013). These differences may be because of the selectivity and potency of each compound and the different animal models and treatments employed.…”

“…For instance, although its therapeutic effect may be attributed to its other multiple targets, the moderate HDACi, valproic acid, has already been approved by the FDA for CNS disorders (Chiu et al, 2013). In addition, it is proposed to start a study to treat AD patients with vorinostat (Benito et al, 2015), the first HDACi approved for cancer (Mann et al, 2007). However, besides the toxicity associated with strong inhibition of HDAC class I isoforms (Robers et al, 2015), a single-target drug may only produce limited benefits in complex diseases like AD and, indeed, network models suggest that the partial and simultaneous inhibition of different targets is likely to produce more efficient effects than the use of specific and high-affinity inhibitors (Lehar et al, 2009;Zheng et al, 2014).…”

“…It must be taken into account that gene expression analysis was carried out after the 4-week washout period and, therefore, some of the changes that would be more evident at the end of the treatment may have faded. To reinforce changes associated with functional pathways linked to synaptic plasticity, cell-type-specific transcriptomics should be carried out by sorting neuronal and nonneuronal nuclei as recent studies have demonstrated that HDACis do not have major impact on nonneuronal cells (Benito et al, 2015). Therefore, because of lack of significant results using this conventional analysis, we used a nonparametric approach implemented in the GSEA software (Subramanian et al, 2005).…”

“…It has been proposed that the activation of the cGMP/cAMP-responsive element-binding protein (CREB) pathway, which is crucial for memory formation, may contribute to the amelioration of AD symptoms observed with PDE5 inhibitors in animal models Puzzo et al, 2005). Similarly, histone deacetylase inhibitors (HDACis) have emerged as promising new therapeutic agents for AD (Benito et al, 2015;Kilgore et al, 2010;Ricobaraza et al, 2009). The 18 known HDAC isoforms are divided into four classes (I-IV) and it is not fully clear which HDAC isoforms might be involved in the therapeutic effects of pan-HDACis observed in AD models.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Indirectly enhancing histone acetylation by chronic inhibition of histone deacetylases (HDACs) was able to reverse the cognitive deficits in AD mouse model (Kilgore et al, 2010) and also in aging mouse (Benito et al, 2015). This is consistent the dysregulation of H4K12ac being implicated to mediate cognitive impairment in aged mice (Peleg et al, 2010).…”