Efavirenz as a cholesterol‐targeting drug for AD

Background Cytochrome P450 46A1 (CYP46A1) is the CNS‐specific cholesterol 24‐hydroxylase that controls cholesterol elimination and turnover in the brain. Efavirenz (EFV) is the FDA‐approved reverse transcriptase inhibitor given to HIV subjects at the 600 mg per day dose. We discovered that small doses of EFV allosterically activate CYP46A1 in mice and are evaluating whether CYP46A1 could be a pharmacologic target for Alzheimer’s disease (AD) and EFV as a disease‐modifying anti‐AD medication. Method Clinical and animal studies investigating EFV. Clinical studies include a proof‐of‐concept clinical trial in patients with AD. Animal studies include multiple in vivo and in vitro assessments of 5XFAD mice (an AD model) after the treatment with a small dose (0.1 mg/kg body weight) of EFV. Result A small dose of EFV activates CYP46A1 and improves behavioral performance of 5XFAD mice; the effect on the amyloid b burden is the treatment paradigm‐specific. The omics and other approaches suggest that the CYP46A1 activity modulation affects multiple signaling pathways and processes via the effects on the physicochemical properties of the plasma membranes. EFV analogs were found, which in vitro are even better CYP46A1 activators than EFV. Conclusion All our available data suggest that CYP46A1 is a viable therapeutic target for AD, and EFV could be the first generation medication that targets cholesterol metabolism and turnover in AD. Supported by the NIH AG067552 grant and the Alzheimer’s Drug Discovery Foundation grant GC‐2012681.