Assessment of Novel Rexinoids for Therapeutic Potential in Combating Alzheimer's Disease

Bexarotene is an FDA approved anti‐cancer agent, but more recently this drug has been assessed for its potential as a therapeutic for dementia. Bexarotene may reduce amyloid beta (α□) plaques that are thought to play a role in Alzheimer’s disease pathophysiology, although clinical use of bexarotene causes unwanted side‐effects including hyperlipidemia and hypothyroidism. Bexarotene drives retinoid‐X‐receptor (RXR) homodimerization on the retinoid‐X‐response element (RXRE), as well as facilitating heterodimers with liver‐X‐receptors (LXR) and peroxisome proliferator activated receptor gamma (PPARγ). These RXR‐containing dimers are hypothesized to induce apolipoprotein (ApoE) in glial cells to control lipid and cholesterol homeostasis in the brain. We tested the ability of bexarotene and a panel of novel rexinoids to drive RXR dimerization using dual luciferase reporter assays to assess transcriptional efficiency of these compounds. We employed both RXRE‐mediated reporter assays, as well as a mammalian 2 hybrid system (M2H) to probe the ability of our novel rexinoids to activate RXR signaling. These compounds were also tested as activators of LXRE‐directed transcription, and as inducers of ApoE mRNA in U87 glial cells. Results from these multiple assay systems reveal that our panel of RXR analogs contain compounds with diverse activities, some of which bind to RXR with greater affinity than others, and in some cases can stimulate ApoE expression to a greater extent than bexarotene. These results suggest that chemical modifications to the parent bexarotene chemical scaffold may yield novel analogs with an amplified ability to activate RXR and possibly combat Alzheimer’s disease via a reduction in amyloid beta (α□) plaques. Support or Funding Information Coins For Alzheimer’s Research Trust