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Cited by 303Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

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Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease

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Heslegrave, Amanda, Heywood, Wendy, Paterson, Ross, Magdalinou, Nadia, Svensson, Johan, Johansson, Per, Öhrfelt, Annika, Blennow, Kaj, Hardy, John, Schott, Jonathan, Mills, Kevin, Zetterberg, Henrik·2016·Molecular Neurodegeneration
DOI 10.1186/s13024-016-0071-xPMC PMC4709982
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Abstract

BACKGROUND: The discovery that heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) are risk factors for Alzheimer's disease (AD), with only the apolipoprotein E (APOE) ε4 gene allele conferring a higher risk, has led to increased interest in immune biology in the brain. TREM2 is expressed on microglia, the resident immune cells of the brain and has been linked to phagocytotic clearance of amyloid β (Aβ) plaques. Soluble TREM2 (sTREM2) has previously been measured in cerebrospinal fluid (CSF) by ELISA but in our hands commercial kits have proved unreliable, suggesting that other methods may be required. We developed a mass spectrometry method using selected reaction monitoring for the presence of a TREM2 peptide, which can be used to quantify levels of sTREM2 in CSF. FINDINGS: We examined CSF samples from memory clinics in Sweden and the UK. For all samples the following were available: clinical diagnosis, age, sex, and measurements of the CSF AD biomarkers Aβ42, T-tau and P-tau181. AD patients (n = 37) all met biomarker (IWG2) criteria for AD. Control individuals (n = 22) were cognitively normal without evidence for AD in CSF. We found significantly higher sTREM2 concentration in AD compared to control CSF. There were significant correlations between CSF sTREM2 and T-tau as well as P-tau181. CSF sTREM2 increase in AD was replicated in a second, independent cohort consisting of 24 AD patients and 16 healthy volunteers. CONCLUSION: CSF concentrations of sTREM2 are higher in AD than in controls, and correlate with markers of neurodegeneration. CSF sTREM2 may be used to quantify glial activation in AD.

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Fig. 1 Increased CSF sTREM2 concentration in AD. a shows a cartoon of the TREM2 peptide indicating in red the peptide sequence and location. b SRM-based analysis of sTREM2 levels in AD cases and controls shows sTREM2 present in all samples (n = 59) but a significant increase (p = 0.0457) is observed in AD cases (n = 37). c There is a significant correlation between CSF T-tau and sTREM2 (r = 0.3863 p = 0.0023). This is also seen (d) when comparing P-tau and sTREM2 (r = 0.5331 p = < 0.0001). However, there is no significant correlation between sTREM2 levels and Aβ42 (r = -0.2097 p = 0.1280) (e). Levels of YKL-40 correlate positively with sTREM2 levels (f) (r = 0.3271 p = 0.0204). g In a second cohort we replicate the finding that CSF sTREM2 levels are increased in AD cases (p = 0.0312)
Fig. 1 Increased CSF sTREM2 concentration in AD. a shows a cartoon of the TREM2 peptide indicating in red the peptide sequence and location. b SRM-based analysis of sTREM2 levels in AD cases and controls shows sTREM2 present in all samples (n = 59) but a significant increase (p = 0.0457) is observed in AD cases (n = 37). c There is a significant correlation between CSF T-tau and sTREM2 (r = 0.3863 p = 0.0023). This is also seen (d) when comparing P-tau and sTREM2 (r = 0.5331 p = < 0.0001). However, there is no significant correlation between sTREM2 levels and Aβ42 (r = -0.2097 p = 0.1280) (e). Levels of YKL-40 correlate positively with sTREM2 levels (f) (r = 0.3271 p = 0.0204). g In a second cohort we replicate the finding that CSF sTREM2 levels are increased in AD cases (p = 0.0312)CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Benitez BA, Cruchaga C. TREM2 and neurodegenerative disease. N Engl J Med. 2013;369(16):1567–8.

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Metadata

Authors
Heslegrave, A., Heywood, W., Paterson, R., Magdalinou, N., Svensson, J., Johansson, P., Öhrfelt, A., Blennow, K., Hardy, J., Schott, J., Mills, K., & Zetterberg, H.
Affiliations
  • National Hospital for Neurology and Neurosurgery (GB)
  • University College London (GB)
  • University of Gothenburg (SE)
  • Skaraborg Hospital (SE)
Corresponding author
Heslegrave, Amanda
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2016-01-12
Volume
11
Issue
1
Pages
3-3
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-016-0071-x
PMC
PMC4709982
OpenAlex
W2234866329
Cited by
303
References
40
Citations by year
2026: 13 · 2025: 24 · 2024: 43 · 2023: 24 · 2022: 31 · 2021: 39 · 2020: 34 · 2019: 22 · 2018: 39 · 2017: 24 · 2016: 9
FWCI
17.17
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Wolfson Foundation
  • Alzheimer’s Research UK
  • Svenska Forskningsrådet Formas
  • Biomedical Research Council (GOSH)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
soluble TREM2, Alzheimer's disease, cerebrospinal fluid biomarkers, microglia, neuroinflammation, tau phosphorylation, phosphorylated tau 181, total tau, amyloid-beta, glial activation, multiple reaction monitoring, mass spectrometry quantification
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Membrane Glycoproteins, Middle Aged, Receptors, Immunologic, Risk Factors, Biomarkers, Amyloid beta-Peptides, tau Proteins, Apolipoprotein E4, Plaque, Amyloid

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