Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Ministry of Health, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
Department of Neurology, University Medical School, Göttingen, Germany.
Mol Neurodegener. 2017 Nov 10;12(1):83. doi: 10.1186/s13024-017-0226-4.
YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing.
In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures.
YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer's disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology. CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson's disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations.
Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.
YKL-40（也称为几丁质酶 3 样 1）是一种由炎症、癌症和干细胞产生的糖蛋白。其生理作用尚不完全清楚，但 YKL-40 在几种与炎症过程相关的神经和神经退行性疾病的大脑和脑脊液（CSF）中升高。然而，在痴呆病例中，YKL-40 的精确特征尚不清楚。
在本研究中，我们比较分析了不同病因的神经退行性痴呆患者的大脑和 CSF 样本中的 YKL-40 水平，这些患者的特征是存在皮质病变和疾病特异性神经炎症特征。
YKL-40 在白质中的纤维状星形胶质细胞中正常表达。此外，YKL-40 在散发性克雅氏病（sCJD）中的反应性原浆状皮质和血管周星形胶质细胞以及纤维状星形胶质细胞中高度广泛表达。阿尔茨海默病（AD）中也检测到 YKL-40 水平升高，但在路易体痴呆（DLB）中没有。在 AD 中，YKL-40 阳性星形胶质细胞通常成群出现，通常围绕β-淀粉样斑块，周围有β-淀粉样血管病；它们也随机分布在大脑皮质和白质中。YKL-40 的过度表达似乎是一种临床前事件，如在朊病毒疾病和 AD 病理学的实验模型中所示。在包括神经科对照组（NC）和不同类型痴呆症患者在内的 288 名个体的队列中测量了 CSF YKL-40 水平。与 NC 相比，sCJD（p<0.001，AUC=0.92）和 AD（p<0.001，AUC=0.77）患者的 YKL-40 水平升高，但血管性痴呆（VaD）（p>0.05，AUC=0.71）或 DLB/帕金森病痴呆（PDD）（p>0.05，AUC=0.70）患者没有。此外，使用两个独立的患者队列来验证 sCJD 中 CSF YKL-40 水平的增加。此外，还发现与 PRNP-D178N（致命家族性失眠症）和 PRNP-E200K 突变相关的遗传性朊病毒疾病中 YKL-40 水平升高。
我们的结果明确表明，在神经退行性痴呆中，YKL-40 是神经炎症的特异性标志物，在朊病毒疾病中其水平最高。因此，YKL-40 的定量分析可能具有在具有神经炎症成分的痴呆症治疗干预评估中的应用潜力。
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