Small molecule TBTC as a new selective retinoid X receptor α agonist improves behavioral deficit in Alzheimer's disease model mice

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, which is characterized by progressive cognitive impairments. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and either decrease of Aβ production or increase of Aβ clearance is beneficial in the treatment of AD, while Aβ clearance regulation seems to be more attractive as a promising therapeutic strategy against AD based on the fact that the insufficient clearance of Aβ is tightly associated with the late onset of AD that is represented as the majority of AD cases. Here, we report that the small molecular compound, methyl 2-amino-6-(tert-butyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (TBTC), as a selective agonist of retinoid X receptor α (RXRα) can effectively activate the heterodimerization of RXRα with either liver X receptor α (LXRα) or peroxisome proliferator activated receptor γ (PPARγ), stimulate the expressions of the genes of apoE, ABCA1 and ABCG1, and decrease Aβ content both in cells and animal models. In addition, administration of TBTC (30mg/kg/day) in the transgenic APP–PS1 mice could also reduce the formation of senile plaques and improve the daily living activity of the mice. Therefore, our findings have suggested that TBTC might hold the potential as a drug lead compound for the treatment of AD.