1 research outputs found
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 Aβ
degradation in the brain. Enhancing the process of Aβ clearance
is an attractive potential AD therapy. Treatment with LXR agonists
may reduce Aβ levels in vivo. However, the clinical potential
of many LXR agonists is limited because of their nonselective actions
on LXRα/β, which lead to undesired hepatic lipogenesis
via LXRα-dependent pathways. In this study, ABCA1 up-regulators
were identified from a series of flavonoids and were found to preferentially
activate LXRβ and up-regulate expression of ABCA1 and apoE in
different cell lines. Further investigations confirmed that these
compounds facilitate intracellular Aβ clearance in Aβ-loaded
BV2 cells. Administration of compound <b>19</b> reduced total
brain Aβ 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