Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease

Bekris, Lynn M.; Khrestian, Maria; Dyne, Eric; Shao, Yvonne; Pillai, Jagan A.; Rao, Stephen M.; Bemiller, Shane M.; Lamb, Bruce T.; Fernández, Hubert H.; Leverenz, James B.

doi:10.1016/j.jneuroim.2018.03.003

Cited by 75 publications

(85 citation statements)

References 61 publications

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“…While the observed basophilia has been reported in DS 50 , significantly decreased lymphocyte count and elevated (or trending towards elevated) neutrophils has been reported in AD 51,52 . Our previous work showed a relationship between plasma sTREM2 and CRP in AD-related mild cognitive impairment (pre-dementia), 27 that was not replicated in this DS pre-dementia cohort. There might be multiple reasons for this that warrant further study.…”

Section: Discussioncontrasting

confidence: 72%

“…Plasma sTREM2 was significantly elevated in DS, in agreement with previously described elevation of sTREM2 in DS sera from young adults with DS prior to dementia onset 33 . Interestingly, sTREM2 is elevated in cerebrospinal fluid in the mild cognitive impairment stage of AD and in early onset forms of AD, but not in peripheral biofluids, such as plasma 24,25,27,28,54 . The elevation of sTREM2 in young DS pre-dementia in plasma and sera suggests that peripheral sTREM2 may increase very early in individuals with elevated Aβ.…”

Section: Discussionmentioning

confidence: 98%

“…Plasma soluble TREM2 (sTREM2) levels were measured using a Luminex 200 3.1 xPONENT System (EMD Millipore, Chicago, IL, USA) and a custom detection method designed to capture the soluble portion of TREM2 protein as previously described 27 HNABTMAG-68K and HCYTMAG60PMX41BK, respectively) following the manufacturer's instructions for analyte detection in human plasma. The inflammatory markers in the panel were: Epidermal Growth Factor (EGF), Fibroblast Growth Factor 2 (FGF-2), eotaxin, Transforming Growth Factor alpha (TGF-α), Granulocyte-colony stimulating factor (G-CSF), FMS-like tyrosine kinase 3 ligand (Flt-3L), Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF), Fractalkine (also known as CX3CL1), interferon (IFN) alpha 2 (IFNα2), IFNγ, growth-regulated oncogene (GRO), interleukin (IL) 10, (IL-10), Monocyte chemotactic protein-3 (MCP-3), IL-12 40kDa (IL-12p40), Macrophage-derived chemokine (MDC), IL-12 70kDa (IL-12P70), IL-13, IL-15, soluble CD40-ligand (sCD40L), IL-17A, IL-1 receptor agonist (IL-1RA), IL-1α, IL-9, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, interferon-gamma inducible protein 10 kDa (IP-10), Monocyte chemoattractant protein (MCP) 1 (MCP-1, also known as CCL2), MCP-3 (also known as CCL7), macrophage inflammatory protein (MIP) 1α (MIP-1α also known as CCL3), MIP-1β (also known as CCL4), tumor necrosis factor (TNF) alpha (TNFα), TNFβ), and Vascular Endothelial Growth Factor (VEGF).…”

Section: Plasma Biomarkersmentioning

confidence: 99%

“…Loss-of-function genetic variants in TREM2, located on chromosome 6, are risk factors for AD and other neurodegenerative diseases [21][22][23] . The soluble cleavage product of TREM2 (sTREM2) is elevated in AD cerebrospinal fluid and positively correlates with Aβ and cognitive decline [24][25][26][27][28][29][30][31][32] . There is relatively little information about TREM2 in DS, though one group describes elevated sTREM2 in young adults and declining levels with aging 33,34 .…”

Section: Introductionmentioning

confidence: 99%

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Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Weber

Koenig

Khrestian

et al. 2019

Preprint

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Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) -related neuropathology, characterized by amyloid plaques with amyloid β (Aβ) and neurofibrillary tangles with tau accumulation more frequently and at an earlier age than their neurotypical counterparts. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 (TREM2) genetic variants are risk factors for AD and other neurodegenerative diseases. A soluble cleavage product of TREM2 (sTREM2) has been described as elevated in AD cerebrospinal fluid and positively correlates with Aβ and cognitive decline. There is relatively little information about TREM2 in DS. The objective of this study was to examine the relationship between sTREM2 and inflammatory markers in DS, prior to the development of dementia symptoms. Since TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS pre-dementia (n=15, mean age 29.5 years) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared to neurotypical, agematched controls (n=16, mean age 29.6 years). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. In addition, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, while there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the group with DS and controls, supporting the hypothesis that its function is altered in people with DS predementia. This exploratory study provides a basis for future studies investigating the relationship between TREM2 and the broader immune response pre-dementia.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 98%

Section: Plasma Biomarkersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Weber

Koenig

Khrestian

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…However, when considering using peripheral inflammatory biomarkers for detecting asymptomatic phases of AD, it has to be taken into account that the alteration of these molecules is common to diverse neurodegenerative disease; thus, it is necessary to correlate their levels with other markers [282,285,286]. Nevertheless, these markers together with other characteristics of AD could serve as a peripheral panel that is useful to distinguish early AD from other neurodegenerative diseases.…”

Section: Marker Of Neuroinflammation For Ad Diagnosismentioning

confidence: 99%

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

Argentati

Tortorella

Bazzucchi

et al. 2020

JPM

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Nowadays, the amyloid cascade hypothesis is the dominant model to explain Alzheimer’s disease (AD) pathogenesis. By this hypothesis, the inherited genetic form of AD is discriminated from the sporadic form of AD (SAD) that accounts for 85–90% of total patients. The cause of SAD is still unclear, but several studies have shed light on the involvement of environmental factors and multiple susceptibility genes, such as Apolipoprotein E and other genetic risk factors, which are key mediators in different metabolic pathways (e.g., glucose metabolism, lipid metabolism, energetic metabolism, and inflammation). Furthermore, growing clinical evidence in AD patients highlighted the presence of affected systemic organs and blood similarly to the brain. Collectively, these findings revise the canonical understating of AD pathogenesis and suggest that AD has metabolic disorder features. This review will focus on AD as a metabolic disorder and highlight the contribution of this novel understanding on the identification of new biomarkers for improving an early AD diagnosis.

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Reduced TREM2 activation in microglia of patients with Alzheimer's disease

et al. 2021

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Loss‐of‐function variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing Alzheimer's disease (AD). The mechanism through which TREM2 contributes to the disease (TREM2 activation vs inactivation) is largely unknown. Here, we analyzed changes in a gene set downstream of TREM2 to determine whether TREM2 signaling is modified by AD progression. We generated an anti‐human TREM2 agonistic antibody and defined TREM2 activation in terms of the downstream expression changes induced by this antibody in microglia developed from human induced pluripotent stem cells (iPSC). Differentially expressed genes (DEGs) following TREM2 activation were compared with the gene set extracted from microglial single nuclear RNA sequencing data of patients with AD, using gene set enrichment analysis. We isolated an anti‐TREM2‐specific agonistic antibody, Hyb87, from anti‐human TREM2 antibodies generated using binding and agonism assays, which helped us identify 300 upregulated and 251 downregulated DEGs. Pathway enrichment analysis suggested that TREM2 activation may be associated with Th2‐related pathways. TREM2 activation was lower in AD microglia than in microglia from healthy subjects or patients with mild cognitive impairment. TREM2 activation also showed a significant negative correlation with disease progression. Pathway enrichment analysis of DEGs controlled by TREM2 activity indicated that TREM2 activation in AD may lead to anti‐apoptotic signaling, immune response, and cytoskeletal changes in the microglia. We showed that TREM2 activation decreases with AD progression, in support of a protective role of TREM2 activation in AD. In addition, the agonistic anti‐TREM2 antibody can be used to identify TREM2 activation state in AD microglia.

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Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease

Cited by 75 publications

References 61 publications

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome

The Other Side of Alzheimer’s Disease: Influence of Metabolic Disorder Features for Novel Diagnostic Biomarkers

Reduced TREM2 activation in microglia of patients with Alzheimer's disease

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