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

Abstract

After 15 years of research into Alzheimer's disease (AD) therapeutics, including billions of US dollars provided by federal agencies, pharmaceutical companies, and private foundations, there are still no meaningful therapies that can delay the onset or slow the progression of AD. An understanding of the proteolytic processing of amyloid precursor protein (APP) and the hypothesis that pathogenic mechanisms in familial and sporadic forms of AD are very similar led to the assumption that pharmacological inhibition of secretases or immunological approaches to clear amyloid depositions in the brain would have been the core to drug discovery strategies and successful therapies. However, there are other understudied approaches including targeting genes, gene networks, and metabolic pathways outside the proteolytic processing of APP. The advancement of newly developed sequencing technologies and mass spectrometry, as well as the availability of animal models expressing human apolipoprotein E isoforms, has been critical in rationalizing additional AD therapeutics. The purpose of this review is to present one of those approaches, based on the role of ligand‐activated nuclear liver X and retinoid X receptors in the brain. This therapeutic approach was initially proposed utilizing in vitro models 15 years ago and has since been examined in numerous studies using AD‐like mouse models. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

Large-scale genomic data-mining implicates dysregulated nuclear receptor-mediated signaling in mental illness

“…Notably, > 20% of NTC genes in GWS loci are associated with two or more PDs (e.g., EP300 and ESR2). A similar overlap was seen for non-psychiatric traits whose biology is closely interlinked with NR-mediated signaling [97][98][99][100][101][102][103][104] [Supplementary Table 7].…”

“…While not taking into the account the significant genetic overlap between PDs [5] , these associations remained significant for MDD and BPD even after adjusting for multiple testing by applying a conservative Bonferroni correction [Figure 2]. When we applied the same approach to summary statistics from non-PD GWASs where NR-mediated signaling has been reported to play a role [97][98][99][100][101][102][103][104] , a very significant association was seen for the NR coregulator subset in height and BMI, as well as a moderate significant association of the NR coregulator subset to HF (Supplementary Figure 1; P = 0.002). For COVID-19 (positive vs. population), in which NR biology plays no obvious role, no association was observed [Supplementary Figure 1].…”

Systems analysis reveals ageing-related perturbations in retinoids and sex hormones in Alzheimer’s and Parkinson’s diseases

“…Further, our zebrafish analysis highlighted the importance of retinoids in ageing of the brain and the skin ( Figure 5C , Table 5 , Supplementary data 6 ). Retinol, its derivatives, and its analogues are already used as topical anti-ageing therapies for aged skin (Riahi et al, 2016), and there is a growing body of evidence suggesting its efficacy for the treatment of AD (Shudo et al, 2009; Fukasawa et al, 2012; Das et al, 2019; Fitz et al, 2019). We add to the body of evidence with this in silico investigation involving zebrafish telomerase mutants, suggesting that the source of retinoid depletion in AD and PD is ageing-related.…”

Therapeutics for dementia and Alzheimer's disease: New directions for precision medicine

“…Lastly, the known risk factor association of APOE as well as other regulators of lipid processes identified in patient GWAS studies (e.g., Clusterin and ATP binding cassette subfamily A member 7 [ABCA7]), has emphasized lipid homeostasis as another area of interest for drug discovery. Despite prior concerns related to undesirable side effects with agonists of the liver X (LXR) and retinoid X (RXR) receptors that transcriptionally regulate cholesterol metabolism and inflammation, Fitz, Nam, Koldamova, and Lefterov () rationalize the development of a second generation therapeutic approach with greater isoform selectivity to these receptors.…”