P4‐026: Allopregnanolone Promotes Cholesterol and Amyloid‐Beta Clearance Mechanisms: Assessment of a Regenerative Therapeutic for Alzheimer’s Disease

Abstract

We aim to develop Allopregnanolone (Allo) as the first regenerative therapeutic for Alzheimer’s disease (AD). Allo reduces amyloid-beta (Aβ) and neuroinflammatory burden while promoting cholesterol homeostasis via mechanisms that promote the liver-X-receptor (LXR) and pregnane-X-receptor (PXR). Crystal structures for PXR/RXRα, LXRβ, and LXRα/RXRβ were accessed from the Protein Data Bank. Docking calculations were carried out using DockingServer. Lipoprotein Signaling and Cholesterol Metabolism gene array and Western blots for protein expression were performed using hippocampus and cortex tissue from 3xTgAD mouse. The Ki for Allo (LXRβ 0.12 μM, PXR 1.17 μM) was comparable to known ligands for each receptor indicating that the configuration and composition is compatible for each of the receptors. Allo’s established free energy of binding (LXRβ -9.44 kcal/mol, PXR -8.49 kcal/mol) signified favorable protein-ligand associations. Allo decreased expression of OLR1 and PCSK9 that promote cholesterol efflux and reduce inflammation. Allo increased the gene expression of CXCL16, LRP6, HMGSC1, and Cyp51 involved in stimulation of the PI3K/Akt/Erk and Wnt pathways and cholesterol synthesis pathway. STAB2 and Idi2 increased and to reduce inflammation signals. Allo also decreased PCSK9 and AKR1D1 genes to promote cholesterol efflux while decreased ANGPTL3 provides a mechanism for reducing plasma cholesterol levels. Allo increased LXRβ, LDL-R, SORL1, ABCA1, Cyp46a1, and decreased NF-κB prot…