Early increase of CSF sTREM2 in Alzheimer’s disease is associated with tau related-neurodegeneration but not with amyloid-β pathology

Autor: Estrella Morenas-Rodríguez, Kai Schlepckow, Erden Eren, Anja Capell, Nicolai Franzmeier, John Q. Trojanowski, Marc Suárez-Calvet, Michael W. Weiner, Laura Piccio, Celeste M. Karch, Christian Haass, Gernot Kleinberger, Miguel Ángel Araque Caballero, Michael Ewers, Yuetiva Deming, Katrin Fellerer, Leslie M. Shaw, Johannes Levin, Carlos Cruchaga, Brigitte Nuscher
Přispěvatelé: German Research Foundation, Munich Cluster for Systems Neurology, Association for Frontotemporal Degeneration (US), European Commission, National Institutes of Health (US), Fondazione Italiana Sclerosi Multipla, Sociedad Española de Neurología, Instituto de Salud Carlos III
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Aging
Pathology
Neurology
genetics [Alzheimer Disease]
cerebrospinal fluid [Amyloid beta-Peptides]
Neurodegenerative
lcsh:Geriatrics
lcsh:RC346-429
pathology [Alzheimer Disease]
0302 clinical medicine
Cerebrospinal fluid
genetics [Membrane Glycoproteins]
Neuroinflammation
Immunologic
Receptors
80 and over
TREM2
2.1 Biological and endogenous factors
genetics [Receptors
Immunologic]
Aetiology
Receptors
Immunologic
Aged
80 and over
Membrane Glycoproteins
Neurodegeneration
pathology [Nerve Degeneration]
Middle Aged
Alzheimer's disease
cerebrospinal fluid [Alzheimer Disease]
cerebrospinal fluid [Biomarkers]
Neurological
Biomarker (medicine)
Female
Microglia
cerebrospinal fluid [Membrane Glycoproteins]
Alzheimer’s disease
Research Article
medicine.medical_specialty
Amyloid
Clinical Dementia Rating
Clinical Sciences
tau Proteins
03 medical and health sciences
Cellular and Molecular Neuroscience
Alzheimer Disease
ddc:570
Genetics
Acquired Cognitive Impairment
medicine
Humans
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
Aged
Shedding
Neurology & Neurosurgery
Amyloid beta-Peptides
TREM2 protein
human
business.industry
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Alzheimer’s Disease Neuroimaging Initiative
medicine.disease
Brain Disorders
lcsh:RC952-954.6
Cross-Sectional Studies
030104 developmental biology
cerebrospinal fluid [tau Proteins]
Nerve Degeneration
Dementia
Neurology (clinical)
business
Biomarkers
030217 neurology & neurosurgery
Zdroj: Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
Digital.CSIC. Repositorio Institucional del CSIC
instname
Molecular Neurodegeneration
Molecular neurodegeneration 14(1), 1 (2019). doi:10.1186/s13024-018-0301-5
Molecular Neurodegeneration, Vol 14, Iss 1, Pp 1-14 (2019)
Molecular neurodegeneration, vol 14, iss 1
ISSN: 1750-1326
DOI: 10.1186/s13024-018-0301-5
Popis: Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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). MSC received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie action grant agreement No 752310. 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).
Databáze: OpenAIRE
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