Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology
Suárez Calvet, Marc (Ludwig-Maximilians-Universität München)
Morenas-Rodríguez, Estrella (Institut d'Investigació Biomèdica Sant Pau)
Kleinberger, Gernot (Ludwig-Maximilians-Universität München)
Schlepckow, Kai (German Center for Neurodegenerative Diseases (DZNE) Munich)
Araque Caballero, Miguel Ángel (Ludwig-Maximilians-Universität München)
Franzmeier, Nicolai (Ludwig-Maximilians-Universität München)
Capell, Anja (Ludwig-Maximilians-Universität München)
Fellerer, Katrin (Ludwig-Maximilians-Universität München)
Nuscher, Brigitte (Ludwig-Maximilians-Universität München)
Eren, Erden (Ludwig-Maximilians-Universität München)
Levin, Johannes (German Center for Neurodegenerative Diseases (DZNE) Munich)
Deming, Yuetiva (Washington University School of Medicine)
Piccio, Laura (Washington University School of Medicine)
Karch, Celeste M. (Washington University School of Medicine)
Cruchaga, Carlos (Washington University School of Medicine)
Shaw, Leslie M. (University of Pennsylvania)
Trojanowski, John Q.. (University of Pennsylvania)
Weiner, Michael (University of California at San Francisco)
Ewers, Michael (Ludwig-Maximilians-Universität München)
Haass, Christian (Ludwig-Maximilians-Universität München)
Universitat Autònoma de Barcelona

Fecha:	2019
Resumen:	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. The online version of this article (10. 1186/s13024-018-0301-5) contains supplementary material, which is available to authorized users.
Ayudas:	European Commission 752310
Nota:	Altres ajuts: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) within the framework of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy), a DFG funded Koselleck Project (HA1737/16-1 to CH) and the AFTD Biomarker Award (to MSC, JL, ME and CH). [...]. This work was also supported by grants from the National Institutes of Health (R01AG044546, RF1AG053303, RF1AG058501, and U01AG058922), YD was supported by a NIMH institutional training grant (T32MH014877). LP was supported by a grant from the Fondazione Italiana Sclerosi Multipla (FISM 2017/R/20). EM was supported by a grant from the Ad-Hoc Committee for Young Neurologist (Spanish Society of Neurology) and Health Institute Carlos III (funding program for the mobility of the researchers).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Alzheimer's disease ; Biomarkers ; Microglia ; Neurodegeneration ; Neuroinflammation ; Shedding ; TREM2
Publicado en:	Molecular neurodegeneration, Vol. 14 (january 2019) , ISSN 1750-1326

DOI: 10.1186/s13024-018-0301-5
PMID: 30630532

14 p, 1.2 MB

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