Cholesterol homeostasis is impaired in Alzheimer’s disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of AD. Indeed, neuronal cholesterol was linked to the formation of amyloid-β (Aβ) formation and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Further, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with positron emission tomography, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in AD patients – with the ultimate aim to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in AD. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in AD patients.

中文翻译：

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脑胆固醇和阿尔茨海默病：探针和药物开发的挑战和机遇

阿尔茨海默病 (AD) 中的胆固醇稳态受到损害，然而，迄今为止，调节大脑胆固醇生物学的尝试尚未转化为对患者切实的临床益处。最近的几个里程碑式的进展极大地提高了我们对过量神经元胆固醇如何影响 AD 病理生理学的理解。事实上，神经元胆固醇通过最近在机制研究中描述的分子途径与淀粉样蛋白-β (Aβ) 的形成和神经原纤维缠结有关。此外，转化分子成像的显着进步现在使得利用正电子发射断层扫描来探测活人大脑中的胆固醇代谢成为可能，这是未来针对 AD 患者脑胆固醇机制的临床试验的重要先决条件——最终目标开发疾病缓解疗法。这项工作总结了 AD 中脑胆固醇的生物合成、运输和清除如何受到影响的当前概念。此外，随着新兴的转化研究工具不仅支持动物模型而且支持 AD 患者的脑胆固醇生物学评估，人们对当前通过药物疗法逆转这些改变的策略进行了批判性讨论。