CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice
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Efavirenz, the FDA-approved anti-retroviral medication, is evaluated in the clinical trial in patients with mild cognitive impairment or early dementia due to Alzheimer’s disease. Efavirenz is 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. The present study tested efavirenz on 5XFAD mice (an Alzheimer’s model) at a very low daily dose of 0.1 mg/kg body weight. Efavirenz treatment started from three months of age, after amyloid plague appearance, and continued for 6 months. This treatment led to CYP46A1 activation in the brain, enhancement of brain cholesterol turnover, behavioral improvements, reduction in microglia activation but increased astrocyte reactivity. The levels of the soluble and insoluble amyloid 40 and 42 peptides were unchanged while the number and area of the dense core amyloid plaques were slightly decreased. The measurements of the brain levels of several pre- and post-synaptic proteins (Munc13-1, PSD-95, gephyrin, synaptophysin, synapsin-1, and calbindin-D28k) suggested efavirenz effect at the synaptic level. Efavirenz treatment in the present work seems to represent a model of behavioral and other improvements independent of the levels of the amyloid peptides and provides insight into potential outcomes of the future clinical trial.
Key WordsCYP46A1 Efavirenz Alzheimer’s disease 24-hydroxycholesterol Astrocytes Microglia Synaptic proteins
Amyloid β Peptide
Amyloid Precursor Protein
Cytochrome P450 46A1
Glial Fibrillary Acidic Protein
Ionized Calcium Binding Adaptor Molecule 1
Liver X Receptor
Morris Water Maze
Phosphate Buffer Saline
This work was supported in part in by National Institute of General Medical Sciences grant GM062882 (IAP). The authors thank the Visual Sciences Research Center Core Facilities (supported by National Institutes of Health Grant P30 EY11373) for assistance with mouse breeding (Heather Butler and Kathryn Franke), animal genotyping (John Denker), tissue sectioning (Catherine Doller), and microscopy (Anthony Gardella). We are also grateful to Dr. Hiroyuki Arakawa for behavioral testing.
IAP conceived and designed the study; ML, NM, JM, YL, and EM performed the experiments; IP, NM, AMP, and ML analyzed the data; IAP and AMP wrote the paper; IAP acquired funding.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflict of interest.
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