LXR-beta Selective Agonists

It is widely held that soluble Aβ oligomers are the most neurotoxic form of Aβ and that a compromised Aβ clearance rate in the brain may be one cause for late-onset Alzheimer’s disease. Key proteins that mediate Aβ clearance, are ApoE and the ABCA1 lipid transporter. Recent studies from multiple laboratories have demonstrated that ligand induced activation of nuclear LXR receptors can induce ApoE and ABCA1 gene expression, leading to reduced levels of neurotoxic Aβ and neuroinflammation. Remarkably, activation of LXR receptors also led to the reversal of behavioral deficits in mouse models.

There are two isoforms of LXR (LXRα and LXRβ; derived from distinct genes) and the LXR agonists that have been tested in mouse models thus far activate both LXR isoforms similarly. Most importantly, recent genetic and pharmacological work has shown that while both LXR isoforms induce ApoE and ABCA1 gene expression, the most significant side effects of LXR action (hypertriglyceridemia and hepatic steatosis) are primarily mediated by the LXRα isoform. Another difficulty is the poor brain penetration with current LXR agonists, leading to high dosage requirements and additional side-effect risks.

Acelot therefore applies the JPS approach to identify novel LXR agonists that are highly LXRβ selective and brain penetrant as potential therapeutic agents to combat Alzheimer’s disease.

All lead candidates are currently being tested in further in-vitro assays.

Please contact us if you are interested in partnering for this project.

(This work is funded in part by the National Science Foundation.)