Department of Molecular Medicine, UF Scripps, Jupiter, FL 33458, USA; Department of Neuroscience, UF Scripps, Jupiter, FL 33458, USA.
The Scripps Research Institute, Jupiter, FL 33458, USA.
Pharmacol Ther. 2023 Sep;249:108486. doi: 10.1016/j.pharmthera.2023.108486. Epub 2023 Jun 29.
Neurodegeneration and its loss of cognitive function is associated with inflammation and an accumulation of lipids. In the periphery, cholesterol's uptake drives a major component of chronic inflammation. In this perspective, we describe the cellular and molecular roles of cholesterol in neuroinflammation and contrast them with those in the periphery. Incorporating shared mechanisms from the periphery, cholesterol emerges as a central signal originating in astrocytes and connecting inflammatory escalation in neurons and microglia. A cholesterol uptake pathway is proposed for neuroinflammation, and we speculate on the binding of cholesterol transport protein apolipoprotein E (apoE), including the Christchurch mutant (R136S), to cell surface receptors as a potential protective modality against uptake of astrocyte cholesterol and escalated neuroinflammation. Lastly, we discuss the molecular basis of cholesterol signaling through nanoscopic clustering and peripheral sources of cholesterol after opening of the blood brain barrier.
神经退行性变及其认知功能的丧失与炎症和脂质积累有关。在周围组织中，胆固醇的摄取驱动了慢性炎症的主要成分。在这方面，我们描述了胆固醇在神经炎症中的细胞和分子作用，并将其与周围组织中的作用进行了对比。从周围组织中整合共同的机制，胆固醇作为一种源自星形胶质细胞的中枢信号出现，并将神经元和小胶质细胞中的炎症升级联系起来。提出了一种胆固醇摄取途径用于神经炎症，我们推测胆固醇转运蛋白载脂蛋白 E（apoE），包括克赖斯特彻奇突变体（R136S），与细胞表面受体的结合作为一种潜在的保护模式，以防止星形胶质细胞胆固醇摄取和神经炎症升级。最后，我们讨论了胆固醇信号通过纳米级聚类和血脑屏障开放后的外周胆固醇来源的分子基础。
