The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions. In vitro, the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) downregulates CYP46A1 expression, while overexpression of CYP46A1 or its pharmacological activation in mouse CP organ cultures increases resilience to TNF-α. In vivo, overexpression of CYP46A1 in the CP in transgenic mice with amyloidosis is associated with better cognitive performance and decreased brain inflammation. Our findings suggest that CYP46A1 expression in the CP impacts the role of this niche as a guardian of brain immune homeostasis.

脉络丛（CP）在健康、衰老和疾病中远程控制大脑功能方面发挥着关键作用。在这里，我们报道CP上皮细胞表达大脑特异性胆固醇24-羟化酶（CYP46A1），并且其水平在不同的小鼠和人类大脑条件下降低，包括淀粉样变性、衰老和SARS-CoV-2感染。使用原代小鼠 CP 细胞培养物，我们证明 CYP46A1 的酶产物 24( S )-羟基胆固醇可下调 CP 内的炎症转录组特征，在多种神经系统疾病中发现炎症转录组特征升高。在体外，促炎细胞因子肿瘤坏死因子 α (TNF-α) 下调 CYP46A1 表达，而 CYP46A1 在小鼠 CP 器官培养物中的过度表达或其药理激活可增加对 TNF-α 的抵抗力。在体内，患有淀粉样变性的转基因小鼠的 CP 中 CYP46A1 的过度表达与更好的认知能力和减少的脑部炎症有关。我们的研究结果表明，CP 中 CYP46A1 的表达会影响该生态位作为大脑免疫稳态守护者的作用。