Latorre-Leal M, Rodriguez-Rodriguez P, Franchini L, Nikolidakis O O, Daniilidou M, Delac L, Varshney MK, Arroyo-García LE, Eroli F, Winblad B, Blennow K, Zetterberg H, Kivipelto M, Pacciarini M, Wang Y, Griffiths WJ, Björkhem I, Matton A, Nalvarte I, Merino-Serrais P, Cedazo-Minguez A, Maioli S. CYP46A1-mediated cholesterol turnover induces sex-specific changes in cognition and counteracts memory loss in ovariectomized mice. Science Advances, Jan 24, 2024 Science Advances
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Vrije Universiteit Amsterdam
This is an interesting study by the Maioli lab, with possibly important implications for stratifying patients in AD trials with cholesterol-targeting interventions. Over the last year, our understanding of the links between cholesterol, AD risk genes, and AD pathogenesis has increased, but there are still many unknowns. One major unknown is how altered cholesterol metabolism in the brain affects steroid hormones. In the brain, cholesterol at the ER can be stored (as cholesteryl esters) or secreted (as 24-hydroxycholesterol). Alternatively, cholesterol enters mitochondria, where it is an essential building block for many (less studied) bioactive compounds including sex hormones.
Thus, the logical prediction is that, when cholesterol metabolism is changed—by AD risk genes or through cholesterol-targeting interventions as in this manuscript—these steroid hormones will also change. Indeed, the authors find such a correlation and give an example on how this linkage between cholesterol metabolism and hormones can affect the outcome of an intervention targeting cholesterol metabolism. They show that CYP46A1 activation can enhance estrogen signaling and rescue cognitive impairments induced by ovariectomy in females, but has little effect in gonadectomized males. Also important for clinical trial designs is that CYP46A1 overexpression improved cognition in female mice, but worsened cognition in males and caused anxiety-like behavior.
How well this translates to humans is of course the big question. CYP46A1 overactivation is a very strong way of inducing conversion of cholesterol to 24-hydroxycholesterol, and it is unclear how this relates to pharmacological activation of CYP46A1 by, e.g., efavirenz. We are currently pursuing CYP46A1 activation by low-dose efavirenz in an early dose-finding Phase 2a clinical trial. Based on the data in this paper, it seems important for possible later trials to take sex into account when evaluating the effects of pharmacological CYP46A1 activation on cognition.
I also find this paper interesting as it defines some of the molecular pathways by which sex (through differences in cholesterol handling towards neurosteroid hormones) might contribute to AD risk and pathogenesis.
View all comments by Rik van der KantCase Western Reserve University
This is an interesting study to obtain additional insight into the higher prevalence of Alzheimer’s disease in women than men. Mice with transgenic CYP46A1 overexpression were used, and sex-specific behavioral changes were correlated with dendritic spine morphology, the levels of synaptic proteins, and activation of estrogen signaling in female brain during aging. Subsequent analyses of the human CSF samples suggested female-specific effects of the CYP46A1 product 24-hydroxycholesterol on t-tau.
The data obtained align well with our previous finding that efavirenz-mediated activation of CYP46A1 in 5XFAD mice, hence brain 24-hydroxycholesterol levels, affect steroidogenesis in the brain, at least in male mice (Mast et al, 2020).
Yet we found a decrease in efavirenz-treated 5XFAD male mice in the levels of pregnenolone, the precursor of all steroid hormones, and therefore, of dehydroepiandrosterone, the precursor of estradiol and testosterone, and estradiol. Testosterone was below the limits of detection by gas chromatography-mass spectrometry. This is in contrast to increased levels of dihydroxytestosterone in aged CYP46A1 transgenic male mice. Further studies are required to clarify if a different pattern of changes as a result of increased brain 24-hydroxycholesterol levels is due to differences between CYP46A1 transgenic expression versus pharmacologic CYP46A1 activation, steroid measurements in the brain hippocampus versus whole brain, age of 9 months versus 18 months, and use of ELISA versus gas chromatography-mass spectrometry for steroid quantifications.
Also, the authors did not measure estradiol, which is well detected in the male brain, and did not consider steroid hormone sulfation, which affects the biological activities of many steroids, including estradiol.
Of importance is that in mice, but not humans, Cyp46a1 mRNA is also detected in testes, yet the protein product was not detected (Lund et al, 1999). Accordingly, it is conceivable that transgenic CYP46A1 overexpression in mice leads to protein expression in testes and affects systemic levels of testosterone, consistent with the author’s data on decreased serum levels of 24-hydroxycholesterol in gonadectomized male mice. Thus, caution should be exercised while interpreting the data in male mice and relating them to humans.
Despite certain issues that need to be clarified, the study’s main message–24-hydroxycholesterol effects should be assessed in both female and male mice; women and men–is well supported. We have a pharmacologic tool, low-dose efavirenz, to allosterically activate CYP46A1 and brain cholesterol turnover in the brain of humans (Lerner et al., 2022).
References:
Mast N, El-Darzi N, Petrov AM, Li Y, Pikuleva IA. CYP46A1-dependent and independent effects of efavirenz treatment. Brain Commun. 2020;2(2):fcaa180. Epub 2020 Oct 29 PubMed.
Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7238-43. PubMed.
Lerner AJ, Arnold SE, Maxfield E, Koenig A, Toth ME, Fortin B, Mast N, Trombetta BA, Denker J, Pieper AA, Tatsuoka C, Raghupathy S, Pikuleva IA. CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer's disease. Alzheimers Res Ther. 2022 Dec 29;14(1):198. PubMed.
View all comments by Irina PikulevaMake a Comment
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