Synthesis and identification of new flavonoids targeting liver X receptor β involved pathway as potential facilitators of Aβ clearance with reduced lipid accumulation.

Alzheimer's disease (AD) is associated with impaired A beta degradation in the brain. Enhancing the process of A beta clearance is an attractive potential AD therapy. Treatment with LXR agonists may reduce A beta levels in vivo. However, the clinical potential of many LXR agonists is limited because of their nonselective actions on LXR alpha/beta, which lead to undesired hepatic lipogenesis via LXR alpha-dependent pathways. In this study, ABCA1 up-regulators were identified from a series of flavonoids and were found to preferentially activate LXR beta and up-regulate expression of ABCA1 and apoE in different cell lines. Further investigations confirmed that these compounds facilitate intracellular A beta clearance in A beta-loaded BV2 cells. Administration of compound 19 reduced total brain A beta and plaque burden in APP/PS1 double transgenic mice, associated with elevated ABCA1 and apoE expression. Compared with the nonselective LXR agonists, the active compounds reported here induced less accumulation of undesired lipids and triglycerides in HepG2 cells.