Retinoid X Receptor Alpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce β-Amyloid Plaques in Alzheimer’s Disease Mouse Model

Abstract

Bexarotene, an agonist of retinoid X receptor alpha (RXRα), has been shown to increase the expression of apoE, ABCA1 and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid β (Aβ)-protein clearance in the brain of an Alzheimer's Disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRα. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methyl, hydroxyl, and methoxy groups in 2- or 4- position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxy in position 2 were more potent to activate Gal4-DBD/RXRα-LBD and RXRα homodimer as well as RXRα heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4- position failed to activate RXRα. Consistently, the derivatives with stronger potency of RXRα activation had higher RXRα binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Aβ plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4- position was the better site for Z-10 modification as to RXRα transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Aβ plaques in AD mouse model.

Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters

“…Bexarotene was used as a standard inducer of ABCA1 / Abca1 via the RXR pathway in several studies. 271 , 272 , 280 , 319 , 380 Induction of Abca1 mRNA and ABCA1 protein levels was maximal for bexarotene in combination with TO901317. 280 Bexarotene is of particular practical relevance as a potential treatment against AD due to its in vivo effects.…”

“… 297 , 383 This prospect led to synthetic bexarotene derivatives, specifically Z10 and Z36. 380 Both candidates induced ABCA1 protein expression by RXR-α activation and reduced Aβ burden in the hippocampus of female APP /PS1 mice. This coincided with an enhanced ABCA1 protein expression in BV2 cells.…”

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches

“…Bexarotene, an RXR agonist ( Gaunt et al, 2021 ), is an FDA-approved drug that stimulates both LXR and peroxisome proliferator-activated receptor gamma (PPAR-γ) pathways. Its administration to transgenic mouse models of AD produced conflicting results regarding its ability to reduce Aβ plaque numbers and slow cognitive decline ( Cramer et al, 2012 ; Tai et al, 2014 ; Balducci et al, 2015 ; Skerrett et al, 2015 ; Muñoz-Cabrera et al, 2019 ; Ren et al, 2019 ). The differing results in these studies may have been due to differences in the rate of development or extent of Aβ pathology between the mouse models, or differing Bexarotene doses or timing of its administration.…”

“…Other regulators of ABCG1 include peroxisome proliferator-activated receptor (PPAR)-delta activators such as pioglitazone ( Cocks et al, 2010 ), cellular sterol levels, and acute permeability barrier disruption ( Jiang et al, 2006 , 2010 ). Bexarotene was found to increase the expression of ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers ( Cramer et al, 2012 ; Zhao et al, 2014 ; Ren et al, 2019 ). Other RXR agonists have also been reported to increase ABCG1 expression ( Boehm et al, 1995 ; Jung et al, 2010 ; Chen et al, 2011 ; Okabe et al, 2013 ; Sun et al, 2015 ).…”

Response of soil bacterial community to alpine wetland degradation in arid Central Asia

“…Sulfate respiration was positively correlated to the contents of SM, TN, TK AN, above-ground biomass, vegetation coverage, and AK (Figure 8). This means that environmental factors play a key role in the process of sulfate respiration (Ren et al, 2018). In addition, the function of bacterial community is closely related to aboveground plants, because aboveground plants provide different survival materials for bacterial community through litter input and root exudates, which further causes the change of bacterial community function (Tolli and King, 2005).…”