Nuclear receptors as therapeutic targets for Alzheimer's disease

Abstract

Introduction: Alzheimer's disease (AD) is characterized by the accumulation and extensive deposition of amyloid β (Aβ) in the parenchyma of the brain. This accumulation of amyloid is associated with perturbations in synaptic function, impairments in energy metabolism and induction of a chronic inflammatory response which acts to promote neuronal loss and cognitive impairment.

Areas covered: Currently, there are no drugs that target the underlying mechanisms of AD. Here, we propose a class of nuclear receptors as novel and promising new therapeutic targets for AD. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiology.

Expert opinion: Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degradation of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. Liver X receptor agonists have proven difficult to move into clinical trials as long-term treatment results in hepatic steatosis. It is our view that PPAR-γ activation remains a promising avenue for the treatment for AD; however, the poor BBB permeability of the currently available agonists and the negative outcome of the Phase III clinical trials are likely to diminish interest in pursuing this target.

Figure 1

In the absence of ligand, type II nuclear receptors heterodimerize with RXR and bind response elements located on the promoters of target genes in association with a corepressor complex actively repressing the expression of target genes (A). In the presence of ligands, the receptor heterodimer undergoes a conformational change, resulting in the exchange of the corepressor complex for a coactivatior complex and allowing for gene transcription (B). Upon ligand binding, PPARɣ becomes sumoylated and recruited to the NFκB-corepressor complex. This interaction secures the corepressor complex on the κBRE promoter elements, preventing its stimulus-induced dismissal and maintains the NFκB inflammatory genes in a repressed state (C).

Figure 2

Activation of nuclear receptors PPARɣ and LXR induce the expression of genes necessary for insulin sensitization and lipid metabolism. Interestingly, activation of PPARɣ induces LXRα and LXRα induces expression of PPARɣ, driving a positive-feedback loop (A). RXR activation induces the activation of their permissive heterodimer binding partners, resulting the expression of both PPARɣ and LXRα target genes (B).