CYP46A1 activation by low dose efavirenz uncovers the link between brain cholesterol metabolism, energetics and vasculature.
Researchers at Case Western Reserve University—led by Irina Pikuleva, PhD, the Carl F. Asseff Professor of Ophthalmology and Visual Sciences—identified brain processes that help explain how CYP46A1 activation by low dose anti-HIV drug efavirenz may benefit different brain disorders. Their findings were recently published in Biomedicine & Pharmacotherapy, a multidisciplinary journal which publishes full-length, original research reports, reviews and preliminary communications.
This work was prompted by the original discovery in Pikuleva’s laboratory of CYP46A1 activation by low-dose efavirenz and a follow up two-site clinical trial of efavirenz in subjects with Alzheimer’s conducted at the University Hospitals and Massachusetts General Hospital.
About the study
CYP46A1 is a CNS-specific enzyme that controls cholesterol elimination and turnover in the brain. Using efavirenz-treated 5XFAD mice, a model of Alzheimer’s disease, the researchers first examined changes in mouse brain proteome, acetylproteome, and metabolome. Then, they conducted targeted measurements of various brain compounds after their in vivo isotopic labeling and imaging of brain vasculature. The data obtained suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enhancement enables increased production of building blocks for cellular and tissue repair, thus mitigating several pathological features, which are common in many neurodegenerative diseases. These results further strengthen targeting CYP46A1 with low-dose efavirenz as a promising therapeutic strategy across a range of neurodegenerative diseases.
