CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease
Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s di...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
|
| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-022-01151-z |
| _version_ | 1797973728210976768 |
|---|---|
| author | Alan J. Lerner Steven E. Arnold Erin Maxfield Aaron Koenig Maria E. Toth Brooke Fortin Natalia Mast Bianca A. Trombetta John Denker Andrew A. Pieper Curtis Tatsuoka Sangeetha Raghupathy Irina A. Pikuleva |
| author_facet | Alan J. Lerner Steven E. Arnold Erin Maxfield Aaron Koenig Maria E. Toth Brooke Fortin Natalia Mast Bianca A. Trombetta John Denker Andrew A. Pieper Curtis Tatsuoka Sangeetha Raghupathy Irina A. Pikuleva |
| author_sort | Alan J. Lerner |
| collection | DOAJ |
| description | Abstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885. |
| first_indexed | 2024-04-11T04:08:58Z |
| format | Article |
| id | doaj.art-be51f0c921904c6eb9b8ba7aa6a50ed7 |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-04-11T04:08:58Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-be51f0c921904c6eb9b8ba7aa6a50ed72023-01-01T12:14:29ZengBMCAlzheimer’s Research & Therapy1758-91932022-12-0114111010.1186/s13195-022-01151-zCYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s diseaseAlan J. Lerner0Steven E. Arnold1Erin Maxfield2Aaron Koenig3Maria E. Toth4Brooke Fortin5Natalia Mast6Bianca A. Trombetta7John Denker8Andrew A. Pieper9Curtis Tatsuoka10Sangeetha Raghupathy11Irina A. Pikuleva12Brain Health and Memory Center, Neurological Institute, University Hospitals Cleveland Medical CenterAlzheimer’s Clinical and Translational Research Unit, Massachusetts General HospitalDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityAlzheimer’s Clinical and Translational Research Unit, Massachusetts General HospitalBrain Health and Memory Center, Neurological Institute, University Hospitals Cleveland Medical CenterAlzheimer’s Clinical and Translational Research Unit, Massachusetts General HospitalDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityAlzheimer’s Clinical and Translational Research Unit, Massachusetts General HospitalDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityHarrington Discovery Institute, University Hospitals Cleveland Medical CenterDepartment of Population and Quantitative Health Sciences, Case Western Reserve UniversityDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityDepartment of Ophthalmology and Visual Sciences, Case Western Reserve UniversityAbstract Background Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. Methods This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain. Results In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects. Conclusions Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology. Trial registration ClinicalTrials.gov, NCT03706885.https://doi.org/10.1186/s13195-022-01151-zCYP46A1EfavirenzAlzheimer’s disease24-HydroxycholesterolStable isotope labeling kinetics |
| spellingShingle | Alan J. Lerner Steven E. Arnold Erin Maxfield Aaron Koenig Maria E. Toth Brooke Fortin Natalia Mast Bianca A. Trombetta John Denker Andrew A. Pieper Curtis Tatsuoka Sangeetha Raghupathy Irina A. Pikuleva CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease Alzheimer’s Research & Therapy CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics |
| title | CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease |
| title_full | CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease |
| title_fullStr | CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease |
| title_full_unstemmed | CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease |
| title_short | CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease |
| title_sort | cyp46a1 activation by low dose efavirenz enhances brain cholesterol metabolism in subjects with early alzheimer s disease |
| topic | CYP46A1 Efavirenz Alzheimer’s disease 24-Hydroxycholesterol Stable isotope labeling kinetics |
| url | https://doi.org/10.1186/s13195-022-01151-z |
| work_keys_str_mv | AT alanjlerner cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT stevenearnold cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT erinmaxfield cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT aaronkoenig cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT mariaetoth cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT brookefortin cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT nataliamast cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT biancaatrombetta cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT johndenker cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT andrewapieper cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT curtistatsuoka cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT sangeetharaghupathy cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease AT irinaapikuleva cyp46a1activationbylowdoseefavirenzenhancesbraincholesterolmetabolisminsubjectswithearlyalzheimersdisease |