Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid- pathology
复制标题
DOI：
10.1186/s13024-018-0301-5
复制
发表时间：
2019-01-10
影响因子：
15.1
通讯作者：
Haass, Christian
中科院分区：
文献类型：
--
作者：
Suarez-Calvet, Marc;Morenas-Rodriguez, Estrella;Haass, Christian
背景TREM 2是一种跨膜受体，主要由中枢神经系统的小胶质细胞表达。TREM 2基因的罕见变异增加了晚发性阿尔茨海默病（AD）的风险。由TREM 2胞外域脱落产生的可溶性TREM 2（sTREM 2）可以在脑脊液（CSF）中检测到，并且是TREM 2介导的小胶质细胞功能的替代指标。先前已报道CSF sTREM 2在AD的不同临床阶段增加，然而，与淀粉样蛋白肽（A）沉积或淀粉样蛋白级联中的另外的病理过程（例如tau病理或神经变性）相关的改变仍不清楚。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，结合临床分期，以检查AD早期无症状和有症状阶段的CSF sTREM 2改变。包括43名携带TREM 2罕见遗传变体的受试者，使用先前验证的酶联免疫吸附测定（ELISA）测量CSF sTREM 2。根据A/T/N框架对ADNI参与者进行分类，我们基于A（1-42）（A）、磷酸化tau（T）和作为神经变性标志物的总tau（N）的CSF水平在由临床痴呆等级（CDR）评分定义的不同临床阶段实施该框架。p.L211P具有比非携带者低的CSF sTREM 2。我们发现，CSF sTREM 2增加在早期症状阶段的晚发性AD，但出乎意料的是，我们观察到降低CSF sTREM 2水平在最早的无症状阶段时，只有异常A病理（A+），但没有tau病理或神经变性（TN-），是present.ConclusionsA病理（A）和tau病理/神经变性（TN）有不同的协会与CSF sTREM 2。虽然tau相关的神经变性与CSF sTREM 2的增加相关，但不存在下游tau相关的神经变性的病理学与CSF sTREM 2的减少相关。
BackgroundTREM2 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 -peptide (A) 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.MethodsA 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 A(1-42) (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.ResultsCSF 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 A pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA 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, A pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.