CYP46A1 Activation by Efavirenz as an Amyloid-Independent Model for Behavioral Improvements in a Preclinical Study on 5XFAD Mice

Abstract

Efavirenz, the FDA-approved anti-retroviral medication, will soon be evaluated in the clinical trial in patients with mild cognitive impairment or early dementia due to Alzheimer's disease. Efavirenz will be assessed for activation of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme that converts cholesterol to 24-hydroxycholesterol. Cholesterol 24-hydroxylation is the major pathway for brain cholesterol removal, and a mechanism that controls brain cholesterol turnover. This clinical trial is based on our previous study, in which efavirenz was administered to 5XFAD mice (an Alzheimer's model) at a very low daily dose of 0.1 mg/kg body weight. Efavirenz treatment started from one month of age, before amyloid plague appearance, and continued for 8 months (the 1st treatment paradigm). This treatment led to CYP46A1 activation in the brain, enhancement of brain cholesterol turnover, reduction in microglia activation, behavioral improvements, as well as a decrease in amyloid beta load in the brain. Herein, we tested another, 2nd, treatment paradigm, in which the same mouse model and efavirenz dose were used except the treatment began at three months of age, after amyloid beta deposition. The treatment continued for 6 months and led to similar beneficial effects as the 1st treatment paradigm, except no reduction in the brain total amyloid beta burden was observed. Mechanistic studies were carried out and suggested efavirenz effect on synaptic glutamatergic transmission. Efavirenz treatment in the present work represents a new model of amyloid-independent behavioral and other improvements and provides insight into potential outcomes of the future clinical trial. Funding Statement: This work was supported in part in by National Institute of General Medical Sciences grant GM062882 (IAP). The funding source did not have any involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the paper; and in the decision to responsibility for the decision to submit for publication. submit the paper for publication. IAP had full access to all the data in the study and had final responsibility for the decision to submit for publication. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All animal experiments were approved by the Case Western Reserve University’s Institutional Animal Care and Use Committee and conformed to recommendations of the American Veterinary Association Panel on Euthanasia.