Shankaran Mahalakshmi, Li Kelvin W, Mohammed Hussein A, Protasio Joan, Fitch Mark, Matthews Marcy, Nyangau Edna, Smith Gordon, Klein Samuel, Eisen Andrew, Turner Scott, Hellerstein Marc K
University of California, Berkeley, CA, USA.
KineMed, Inc., Emeryville, CA, USA.
Mult Scler J Exp Transl Clin. 2025 May 30;11(2):20552173251344555. doi: 10.1177/20552173251344555. eCollection 2025 Apr-Jun.
Cholesterol is an essential and major component of myelin. Brain cholesterol turnover in humans can be studied noninvasively by metabolic labeling of the brain-specific cholesterol metabolite, 24S-hydroxycholesterol (24-OHC), which is released into blood.
We examined the effects on brain cholesterol turnover in healthy individuals and in multiple sclerosis (MS) following treatment with placebo or the remyelinating monoclonal antibody, rHIgM22, which binds to oligodendrocytes and myelin.
synthesis rates of brain cholesterol were measured by label incorporation and die-away of 24-OHC sampled from blood during and after heavy water (DO) intake in age- and sex-matched non-MS and clinically stable relapsing-remitting MS subjects.
Incorporation and die-away of labeled 24-OHC revealed biphasic kinetics, with two kinetically distinct pools of brain cholesterol: a large, slow turnover pool and a smaller, metabolically more active pool of newly synthesized cholesterol. The latter showed significantly higher turnover rates in MS compared to non-MS subjects, which was significantly reduced in patients with MS treated with rHIgM22.
Plasma 24-OHC kinetics provide a minimally invasive biomarker of brain cholesterol metabolism and revealed differences between healthy and clinically stable MS subjects, with increased turnover of the metabolically active 24-OHC pool that normalized in response to rHIgM22 therapy.
胆固醇是髓磷脂的重要主要成分。人类大脑胆固醇的更新可通过对大脑特异性胆固醇代谢物24S-羟基胆固醇（24-OHC）进行代谢标记来无创研究，该代谢物会释放到血液中。
我们研究了安慰剂或与少突胶质细胞和髓磷脂结合的促髓鞘再生单克隆抗体rHIgM22治疗对健康个体和多发性硬化症（MS）患者大脑胆固醇更新的影响。
在年龄和性别匹配的非MS和临床稳定的复发缓解型MS受试者摄入重水（DO）期间及之后，通过标记掺入和从血液中采集的24-OHC的衰减来测量大脑胆固醇的合成率。
标记的24-OHC的掺入和衰减显示出双相动力学，大脑胆固醇有两个动力学上不同的池：一个大的、更新缓慢的池和一个较小的、代谢更活跃的新合成胆固醇池。与非MS受试者相比，后者在MS患者中显示出明显更高的更新率，而接受rHIgM22治疗的MS患者的更新率则显著降低。
血浆24-OHC动力学提供了一种微创的大脑胆固醇代谢生物标志物，并揭示了健康与临床稳定的MS受试者之间的差异，代谢活跃的24-OHC池的更新增加，而rHIgM22治疗后更新恢复正常。
