Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
Mol Neurodegener. 2019 Jan 10;14(1):1. doi: 10.1186/s13024-018-0301-5.
TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.
A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.
CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.
Aβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
TREM2 是一种跨膜受体，主要由中枢神经系统中的小胶质细胞表达。TREM2 基因的罕见变异会增加晚发性阿尔茨海默病（AD）的风险。TREM2 细胞外结构域脱落产生的可溶性 TREM2（sTREM2）可在脑脊液（CSF）中检测到，是 TREM2 介导的小胶质细胞功能的替代测量指标。先前有报道称，CSF sTREM2 在 AD 的不同临床阶段都会增加，然而，与淀粉样β肽（Aβ）沉积或淀粉样级联的其他病理过程（如 tau 病理学或神经退行性变）相关的变化尚不清楚。在目前的横断面研究中，我们采用了 NIA-AA 共识指南最近提出的基于生物标志物的分类框架，并结合临床分期，以检查 AD 的早期无症状和有症状阶段 CSF sTREM2 的变化。
对阿尔茨海默病影像学倡议（ADNI）队列的 1027 名参与者进行了横断面研究，其中包括 43 名携带 TREM2 罕见遗传变异的受试者，使用先前验证的酶联免疫吸附测定法（ELISA）测量 CSF sTREM2。ADNI 参与者根据 A/T/N 框架进行分类，我们根据 CSF 中 Aβ（A）、磷酸化 tau（T）和总 tau 的水平作为神经退行性变的标志物（N）进行分类，这些标志物基于临床痴呆评定量表（CDR）评分定义的不同临床阶段。
TREM2 变异体之间的 CSF sTREM2 不同，而 p.R47H 变异体的 CSF sTREM2 较高，p.L211P 的 CSF sTREM2 低于非携带者。我们发现，在晚发性 AD 的早期有症状阶段，CSF sTREM2 增加，但出乎意料的是，当仅存在异常的 Aβ 病理学（A+）而没有 tau 病理学或神经退行性变（TN-）时，我们观察到最早的无症状阶段 CSF sTREM2 水平降低。
Aβ 病理学（A）和 tau 病理学/神经退行性变（TN）与 CSF sTREM2 有不同的关联。虽然与 tau 相关的神经退行性变与 CSF sTREM2 的增加有关，但在没有下游与 tau 相关的神经退行性变的情况下存在 Aβ 病理学与 CSF sTREM2 的减少有关。
