Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that regulates microglial function and is involved in the pathophysiology of several neurodegenerative diseases. Its soluble form (sTREM2) results from shedding of the TREM2 ectodomain. The role of TREM2 in prion diseases, a group of rapidly progressive dementias remains to be elucidated. In the present study, we analysed the expression of TREM2 and its main sheddase ADAM10 in the brain of sporadic Creutzfeldt-Jakob disease (sCJD) patients and evaluated the role of CSF and plasma sTREM2 as a potential diagnostic marker of prion disease. Our data indicate that, compared to controls, TREM2 is increased in sCJD patient brains at the mRNA and protein levels in a regional and subtype dependent fashion, and expressed in a subpopulation of microglia. In contrast, ADAM10 is increased at the protein, but not the mRNA level, with a restricted neuronal expression. Elevated CSF sTREM2 is found in sCJD, genetic CJD with mutations E200K and V210I in the prion protein gene (PRNP), and iatrogenic CJD, as compared to healthy controls (HC) (AUC = 0.78–0.90) and neurological controls (AUC = 0.73–0.85), while CSF sTREM2 is unchanged in fatal familial insomnia. sTREM2 in the CSF of cases with Alzheimer’s disease, and multiple sclerosis was not significantly altered in our series. CSF sTREM2 concentrations in sCJD are PRNP codon 129 and subtype-related, correlate with CSF 14-3-3 positivity, total-tau and YKL-40, and increase with disease progression. In plasma, sTREM2 is increased in sCJD compared with HC (AUC = 0.80), displaying positive correlations with plasma total-tau, neurofilament light, and YKL-40. We conclude that comparative study of TREM2 in brain and biological fluids of prion diseases reveals TREM2 to be altered in human prion diseases with a potential value in target engagement, patient stratification, and disease monitoring.

髓细胞上表达的触发受体 2 (TREM2) 是一种先天免疫细胞表面受体，可调节小胶质细胞功能，并参与多种神经退行性疾病的病理生理学。其可溶形式 (sTREM2) 是由 TREM2 胞外域脱落引起的。TREM2 在朊病毒疾病（一组快速进展的痴呆症）中的作用仍有待阐明。在本研究中，我们分析了散发性克雅氏病 (sCJD) 患者大脑中 TREM2 及其主要脱落酶 ADAM10 的表达，并评估了脑脊液和血浆 sTREM2 作为朊病毒病潜在诊断标志物的作用。我们的数据表明，与对照组相比，sCJD 患者大脑中的 TREM2 在 mRNA 和蛋白质水平上以区域和亚型依赖性方式增加，并在小胶质细胞亚群中表达。相反，ADAM10 在蛋白质上增加，但在 mRNA 水平上没有增加，神经元表达受限。脑脊液 sTREM2 升高见于 sCJD、遗传性 CJD，在朊病毒蛋白基因中具有 E200K 和 V210I 突变（PRNP ) 和医源性 CJD，与健康对照 (HC) (AUC = 0.78–0.90) 和神经系统对照 (AUC = 0.73–0.85) 相比，而 CSF sTREM2 在致命的家族性失眠症中没有变化。在我们的系列中，阿尔茨海默病和多发性硬化症患者脑脊液中的 sTREM2 没有显着改变。sCJD 中的 CSF sTREM2 浓度为PRNP密码子 129 和亚型相关，与 CSF 14-3-3 阳性、总 tau 和 YKL-40 相关，并随着疾病进展而增加。在血浆中，sCJD 的 sTREM2 与 HC 相比增加（AUC = 0.80），与血浆总 tau、神经丝光和 YKL-40 呈正相关。我们得出结论，对朊病毒疾病的大脑和生物体液中的 TREM2 进行的比较研究表明，TREM2 在人类朊病毒疾病中发生改变，在目标参与、患者分层和疾病监测方面具有潜在价值。