Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity

Abstract

Bexarotene-activated retinoid X receptors (RXRs) ameliorate memory deficits in Alzheimer's disease mouse models, including mice expressing human apolipoprotein E (APOE) isoforms. The goal of this study was to gain further insight into molecular mechanisms whereby ligand-activated RXR can affect or restore cognitive functions. We used an unbiased approach to discover genome-wide changes in RXR cistrome (ChIP-Seq) and gene expression profile (RNA-Seq) in response to bexarotene in the cortex of APOE4 mice. Functional categories enriched in both datasets revealed that bexarotene-liganded RXR affected signaling pathways associated with neurogenesis and neuron projection development. To further validate the significance of RXR for these functions, we used mouse embryonic stem (ES) cells, primary neurons, and APOE3 and APOE4 mice treated with bexarotene. In vitro data from ES cells confirmed that bexaroteneactivated RXR affected neuronal development at different levels, including proliferation of neural progenitors and neuronal differentiation, and stimulated neurite outgrowth. This effect was validated in vivo by demonstrating an increased number of neuronal progenitors after bexarotene treatment in the dentate gyrus of APOE3 and APOE4 mice. In primary neurons, bexarotene enhanced the dendritic complexity characterized by increased branching, intersections, and bifurcations. This effect was confirmed by in vivo studies demonstrating that bexarotene significantly improved the compromised dendritic structure in the hippocampus of APOE4 mice. We conclude that bexarotene-activated RXRs promote genetic programs involved in the neurogenesis and development of neuronal projections and these results have significance for the improvement of cognitive deficits.

Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease

“…Brains from five female and three male mice of each genotype, all 7-10 months old, were removed and snap frozen as described previously (7).…”

“…This hypothesis derives, in part, from evidence that the strongest correlate of cognitive impairment in AD is loss of synapses (3,4), with excitatory synapses onto dendritic spines particularly affected (5)(6)(7). Conversely, in cognitively normal individuals who nevertheless have substantial AD pathology, neuron number and synaptic markers are largely preserved (8).…”

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders

“…Probably through these mechanism agonists of PPAR-α may have a promising effect in a mouse model of aging-dependent cognitive impairments [37,38]. Moreover, it was previously reported that RXR activation increases dendritic complexity and branching of neurons and differentiation [39,40] but it seems now that PPAR-α plays a key role in these processes.…”

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease

“…This effect was validated in a mouse model, demonstrating that following bexarotene treatment, both APOE3 and APOE4 mice had an increased number of neural progenitors in the dentate gyrus. Furthermore, bexarotene significantly improved the compromised dendritic structure in the hippocampus of APOE4 mice (Mounier et al, ). RNA‐Seq data showed an enrichment of Gene Ontology categories related to neuronal differentiation, neurite growth, and neuritogenesis in APOE4 mice treated with bexarotene.…”

“…Interestingly, RNA‐Seq data demonstrated that bexarotene treatment affected Notch1 signalling known to be important in cell fate decisions in uncommitted proliferating cells and differentiation of immature neurons. Additional genes associated with changes in the Notch1 pathway following bexarotene treatment include Dlk1 , nerve growth factor receptor, and EGF receptor (Mounier et al, ). Most studies have demonstrated that adult neurogenesis, particularly in the dentate gyrus, improves behavioural deficits in rodents (reviewed in Lepousez, Nissant, & Lledo, ).…”