The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

ABSTRACT Efavirenz (EFV) is an anti‐HIV drug, and cytochrome P450 46A1 (CYP46A1) is the major brain cholesterol hydroxylase. Previously, we discovered that EFV activates CYP46A1 and improves behavioral performance in 5XFAD mice, an Alzheimer's disease model. Herein, the unbiased omics and other approaches were used to study 5XFAD mice in the amyloid‐decreasing paradigm of CYP46A1 activation by EFV. These approaches revealed increases in the brain levels of postsynaptic density protein 95, gephyrin, synaptophysin, synapsin, glial fibrillary acidic protein, and CYP46A1 and documented altered expression and phosphorylation of 66 genes and 77 proteins, respectively. The data obtained pointed to EFV effects at the synaptic level, plasmin‐depended amyloid clearance, inflammation and microglia phenotype, oxidative stress and cellular hypoxia, autophagy and ubiquitin‐proteasome systems as well as apoptosis. These effects could be realized in part via changes in the Ca2+‐, small GTPase, and catenin signaling. A model is proposed, in which CYP46A1‐dependent lipid raft rearrangement and subsequent decrease of protein phosphorylation are central in EFV effects and explain behavioral improvements in EFV‐treated 5XFAD mice.—Petrov, A. M., Mast, N., Li, Y., Pikuleva, I. A. The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment. FASEB J. 33, 8782–8798 (2019). www.fasebj.org