Assessment of cholesterol homeostasis in the living human brain.
Assessment of cholesterol homeostasis in the living human brain.
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评估活着的人脑中胆固醇稳态。
DOI：
10.1126/scitranslmed.adc9967
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发表时间：
2022-10-05
影响因子：
17.1
通讯作者：
Liang, Steven H.
中科院分区：
文献类型：
--
作者：
Haider, Ahmed;Zhao, Chunyu;Wang, Lu;Xiao, Zhiwei;Rong, Jian;Xia, Xiaotian;Chen, Zhen;Pfister, Stefanie K.;Mast, Natalia;Yutuc, Eylan;Chen, Jiahui;Li, Yinlong;Shao, Tuo;Warnock, Geoffrey, I;Dawoud, Alyaa;Connors, Theresa R.;Oakley, Derek H.;Wei, Huiyi;Wang, Jinghao;Zheng, Zhihua;Xu, Hao;Davenport, April T.;Daunais, James B.;Van, Richard S.;Shao, Yihan;Wang, Yuqin;Zhang, Ming-Rong;Gebhard, Catherine;Pikuleva, Irina;Levey, Allan, I;Griffiths, William J.;Liang, Steven H.
大脑胆固醇稳态的改变广泛涉及神经系统疾病。尽管哺乳动物大脑中胆固醇生物学的控制非常复杂，但过量的神经元胆固醇主要通过细胞色素 P450 46A1 (CYP46A1) 的代谢清除来消除。目前还没有方法可以可视化活人大脑中的胆固醇代谢；因此，一种通过 CYP46A1 定量测量大脑胆固醇代谢程度的非侵入性技术可能会广泛影响疾病的诊断和使用靶向疗法的治疗选择。在这里，我们描述了针对 CYP46A1 的正电子发射断层扫描 (PET) 示踪剂的开发和测试。 18F-CHL-2205(18F-Cholestify)。我们的数据显示，PET 成像读数与 CYP46A1 蛋白表达以及胆固醇在大脑中的代谢程度相关，这是通过对啮齿类动物、非人类灵长类动物和人类样本进行跨物种尸检分析得出的。在完善的阿尔茨海默病 (AD) 3xTg-AD 小鼠模型中提供了体内功效的概念验证，我们在该模型中表明探针对 3xTg-AD 小鼠和对照动物之间脑胆固醇代谢的差异敏感。此外，我们的临床观察表明，与年龄匹配的男性相比，女性通过 CYP46A1 的基线脑胆固醇清除率要高得多。这些发现说明了使用 PET 评估脑胆固醇代谢的巨大潜力，并将 PET 确立为临床上无创评估脑胆固醇稳态的敏感工具。正电子发射断层扫描分子成像现在提供了一种非侵入性评估活人大脑中胆固醇稳态的工具。
Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a non-invasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly impact disease diagnosis and treatment options using targeted therapies. Here we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer. 18F-CHL-2205(18F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species post-mortem analyses of specimens from rodents, non-human primates and humans. Proof-of-concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Further, our clinical observations point towards a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for non-invasive assessment of brain cholesterol homeostasis in the clinic. Molecular imaging with positron emission tomography now provides a tool to non-invasively assess cholesterol homeostasis in the living human brain.
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DOI：
10.3390/antiox10050740
发表时间：
2021-05-07
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Gamba P;Giannelli S;Staurenghi E;Testa G;Sottero B;Biasi F;Poli G;Leonarduzzi G
通讯作者：
Leonarduzzi G
影响因子：
12.4
作者：
Hudry, Eloise;Van Dam, Debby;Cartier, Nathalie
通讯作者：
Cartier, Nathalie
影响因子：
14.5
作者：
Djelti, Fathia;Braudeau, Jerome;Cartier, Nathalie
通讯作者：
Cartier, Nathalie
影响因子：
3.9
作者：
Grayaa, S.;Zerbinati, C.;Iuliano, L.
通讯作者：
Iuliano, L.
影响因子：
4.8
作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert