Haider A, Zhao C, Wang L, Xiao Z, Rong J, Xia X, Chen Z, Pfister SK, Mast N, Yutuc E, Chen J, Li Y, Shao T, Warnock GI, Dawoud A, Connors TR, Oakley DH, Wei H, Wang J, Zheng Z, Xu H, Davenport AT, Daunais JB, Van RS, Shao Y, Wang Y, Zhang MR, Gebhard C, Pikuleva I, Levey AI, Griffiths WJ, Liang SH. Assessment of cholesterol homeostasis in the living human brain. Sci Transl Med. 2022 Oct 5;14(665):eadc9967. PubMed.

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  1. I am familiar with the stellar research of Drs. Liang and Griffith, the senior authors of this study. Their development of a PET tracer for following brain cholesterol metabolism is significant, and, as they note, will allow many mysteries regarding this process to be solved. The work of Ingemar Björkhem in Sweden revealed that the conversion of cholesterol to 24-hydroxycholesterol was a route by which cholesterol could be metabolized in the brains of several mammals, including humans. My group isolated the enzyme that catalyzes this reaction (cholesterol 24-hydroxylase, gene symbol CYP46A1), and together with John Dietschy’s lab, we quantitated how much cholesterol is metabolized in the mouse and showed that disruption of the pathway by knocking out the gene caused learning difficulties in the species.

    Together this research revealed that metabolizing cholesterol in the adult mouse brain is important, but it is not clear why this is so or whether the same is true in humans. The CYP46A1 gene is very highly conserved in vertebrates (at least down to zebra fish), which suggests that it, and the pathway the encoded enzyme catalyzes, are likely important.

    There are several studies in the literature showing that 24-hydroxycholesterol levels in the blood (this product of the brain turnover pathway is secreted from the brain into the bloodstream and thereafter cleared by the liver) are altered in various diseases that affect the central nervous system, again hinting that cholesterol metabolism is important. There is little consensus, however, as to whether these levels are higher or lower than normal, or again, just what these data mean (for a review see Russell et al., 2009). 

    Given these many uncertainties in the field, and the highly conserved nature of the pathway, the PET tracer will be a real game changer. The number of noninvasive studies that can now be done is large, and (finally!) we will be able to learn why we metabolize about 6 mg of cholesterol every day through this route.

    References:

    Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T. Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem. 2009;78:1017-40. PubMed.

    View all comments by David Russell

  2. We are very excited by new developments that can help to monitor cholesterol metabolism in the living human brain. This study is highly impressive because it defines a novel and specific method to measure CYP46A1 levels in the human brain through PET imaging. Whether this novel 18F-CHL-2205 tracer can really be used to monitor changes in brain cholesterol homeostasis, as the title of the article suggests is, however, less clear.

    An increasing number of observations, including our own work in iPSC-derived neurons, have shown that excess levels of cholesterol in neurons can contribute to accumulation of both Aβ and p-tau (van der Kant et al., 2020). Cholesterol accumulates in the brains of AD transgenic mice, where a reduction of cholesterol levels has been shown to ameliorate pathogenesis. A few years back, the group of Irina Pikuleva discovered that low doses of the HIV drug efavirenz enhance cholesterol export from the brain by activating the CNS-specific protein CYP46A1. CYP46A1 converts cholesterol to 24-hydroxycholesterol, which can cross the blood-brain barrier into the blood.

    Based on these findings, and our own findings that CYP46A1 activation by efavirenz reduces p-tau levels in human iPSC-derived neurons and tau transgenic mice (unpublished), we are currently preparing a Phase 2a clinical trial in subjects with MCI or mild dementia due to AD. This dose-finding, randomized, double-blinded, multicenter study will evaluate different low doses of efavirenz and is set to start in spring of 2023. The goal is to define an optimal dose at which efavirenz activates CYP46A1. The primary outcome is target engagement (CYP46A1 activation), which will be indirectly evaluated by measuring the levels of 24-hydroxycholesterol in CSF and blood before, during, and after treatment.

    Methods that can more directly report on brain cholesterol levels, or brain cholesterol metabolism, in AD patients would therefore be of immense value for the field. In this well-crafted paper, the authors show that 18F-CHL-2205 can bind CYP46A1 in healthy volunteers. It is, however, unclear how this informs on cholesterol turnover or metabolism in humans. We have no doubt that information on CYP46A1 protein expression in brain gained by using 18F-CHL-2205 will be of high relevance for research into CYP46A1 biology. However, it is not clear whether 18F-CHL-2205 can be used to compare brain cholesterol levels between individuals (e.g., AD patients versus controls) and/or to monitor changes in brain cholesterol metabolism in response to interventions. This would really have been a game changer in the field.

    We are not planning to incorporate 18F-CHL-2205 PET scans into our trial because we are just finalizing the protocols and aim to start recruitment as soon as possible. 18F-CHL-2205 PET may be of interest for follow-up trials, yet we don’t directly see how information on CYP46A1 levels will help follow cholesterol metabolic changes in the brain. CYP46A1 is not regulated by cholesterol to our knowledge, and we would not expect it to change in the presence of CYP46A1 activators.

    18F-CHL-2205 PET might be helpful in possibly explaining differences among efavirenz responders and nonresponders, but we would assume everybody has some basal level of expression. In this respect it would have also been very interesting to see how CYP46A1 activators, such as efavirenz, alter the binding of 18F-CHL-2205.

    So, while this new tracer will certainly help to better understand CYP46A1 biology, and its relationship to AD pathogenesis, the search for a direct reporter of brain cholesterol levels in Alzheimer's patients continues.

    References:

    van der Kant R, Goldstein LS, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci. 2020 Jan;21(1):21-35. Epub 2019 Nov 28 PubMed.

    View all comments by Everard (Jort) Vijverberg

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  1. A New PET Tracer Could Track Cholesterol Clearance from the Brain