An Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome: A Preliminary Report This information is current as of September 25, 2021. Grace E. Weber, Katherine A. Koenig, Maria Khrestian, Yvonne Shao, Elizabeth D. Tuason, Marie Gramm, Dennis Lal, James B. Leverenz and Lynn M. Bekris J Immunol published online 20 January 2020 http://www.jimmunol.org/content/early/2020/01/17/jimmun Downloaded from ol.1901166 Supplementary http://www.jimmunol.org/content/suppl/2020/01/17/jimmunol.190116 http://www.jimmunol.org/ Material 6.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! 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Published January 20, 2020, doi:10.4049/jimmunol.1901166 The Journal of Immunology An Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome: A Preliminary Report Grace E. Weber,*,1 Katherine A. Koenig,†,1 Maria Khrestian,* Yvonne Shao,* Elizabeth D. Tuason,* Marie Gramm,*,‡ Dennis Lal,* James B. Leverenz,x and Lynn M. Bekris* Individuals with Down syndrome (DS) develop Alzheimer’s disease (AD)–related neuropathology, characterized by amyloid plaques with amyloid b (Ab) and neurofibrillary tangles with tau accumulation. 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. Soluble TREM2 (sTREM2), a soluble cleavage product of TREM2, is elevated in AD cerebro- Downloaded from spinal fluid and positively correlates with cognitive decline. There is relatively little information about TREM2 in DS. Our objective was to examine the relationship between sTREM2 and inflammatory markers in young adults with DS, prior to the development of dementia symptoms. Because 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 predementia (n = 15, mean age = 29.5 y) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared with neurotypical, age-matched controls (n = 16, mean age = 29.6 y). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory http://www.jimmunol.org/ markers. Additionally, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, whereas there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the groups, supporting the hypothesis that its function is altered in people with DS predementia. This preliminary report of human plasma provides a basis for future studies investigating the relationship between TREM2 and the broader immune response predementia. The Journal of Immunology, 2020, 204: 000–000. n the last half of the 20th century, the life expectancy of resulting from three copies of APP leads to Ab plaque depo- individuals with Down syndrome (DS) has increased to sition in ∼50% of people with DS over the age of 30 and by guest on September 25, 2021 I 60 years (1–3), highlighting the importance of understanding subsequently increases their risk for dementia in middle age age-related disease in this population (4). Most individuals with (around age 40) (5, 6). The study of early adulthood in DS DS carry three full copies of chromosome 21. The amyloid potentially provides a unique model for the early biology of precursor protein (APP) gene, located on chromosome 21, is Alzheimer’s disease (AD) in the general population. processedintoamyloidb (Ab). The overabundance of Ab Assessment of subtle cognitive changes is challenging in DS, partly because of the presence and variability of intellectual *Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195; †Imaging Insti- disability (7, 8). Therefore, defining biomarkers of dementia tute, Cleveland Clinic, Cleveland, OH 44195; ‡Cologne Center for Genomics, Univer- x progression is critical in this population of individuals. AD sity of Cologne, 50931 Cologne, Germany; and Cleveland Clinic Lou Ruvo Center for neuropathology, amyloid, and tau accumulate early in DS, and Brain Health, Neurological Institute, Clevland Clinic, Cleveland, OH 44195 plasma Ab and tau represent potential biomarker candidates 1G.E.W. and K.A.K. contributed equally. (9–11). In DS, the variable severity of Ab deposition within age ORCIDs: 0000-0002-4273-7911 (G.E.W.); 0000-0002-1504-7130 (K.A.K.); 0000- 0002-1621-4711 (M.K.); 0000-0003-4125-1351 (E.D.T.). groups and age of onset of dementia suggest that factors other than the presence of triplication of the APP gene contribute to Received for publication September 26, 2019. Accepted for publication December 13, 2019. the timing and severity of amyloid deposition and therefore the This work was supported by U.S. Department of Defense Grant AZ160058, National onset of AD (5, 12–14). Institute on Aging (NIA) Grants P30AG062428, R01 AG046543, and RF1 AG051495, Biomarkers of peripheral inflammation and the innate im- National Institute of Neurological Disorders and Stroke Grant U01 NS100610, NIA mune response are elevated in DS (15–18). Triggering receptor Grants R01 AG057552 and R01 AG022304, the Alzheimer’s Association (2016-NIRG- 395867), and the Jane and Lee Seidman Fund. expressed in myeloid cells 2 (TREM2) is a pattern recognition Address correspondence and reprint requests to Dr. Lynn M. Bekris, Cleveland receptor that can be activated by both pathogen- and danger- Lerner College of Medicine of Case Western Reserve University, Genomic Medicine associated molecular patterns in the innate immune response Institute, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave- (19, 20). Loss-of-function genetic variants in TREM2, located nue, R4, Cleveland, OH 44195. E-mail address: [email protected] on chromosome 6, are risk factors for AD and other neurode- The online version of this article contains supplemental material. generative diseases (21–23). Soluble TREM2 (sTREM2), a solu- Abbreviations used in this article: Ab, amyloid b; AD, Alzheimer’s disease; APP, amyloid precursor protein; CRP, C-reactive protein; DS, Down syndrome; FDR, false ble cleavage product of TREM2, is elevated in AD cerebrospinal discovery rate; Flt-3L, FMS-like tyrosine kinase 3 ligand; GRO, growth-regulated fluid and positively correlates with Ab and cognitive decline oncogene; MDC, macrophage-derived chemokine; sCD40L, soluble CD40-ligand; (24–32). There is relatively little information about TREM2 in sTREM2, soluble TREM2; TREM2, triggering receptor expressed in myeloid cells 2. DS, although one group describes elevated TREM2 protein Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 levels in young adults and declining levels with aging (33, 34). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1901166 2 ALTERED SOLUBLE TREM2 AND CYTOKINES IN DOWN SYNDROME The hypothesis of this investigation was that there is a rela- CCL7), IL-12 40 kDa (IL-12p40), macrophage-derived chemokine (MDC), tionship between sTREM2 and inflammatory markers in DS, prior IL-12 70 kDa (IL-12P70), IL-13, IL-15, soluble CD40-ligand (sCD40L), to the development of dementia symptoms. We found that young IL-17A, IL-1 receptor agonist (IL-1RA), IL-1a,IL-9,IL-1b,IL-2,IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IFN-g inducible protein 10 kDa (IP-10), adults with DS displayed an altered immune profile compared with MCP-1 (also known as CCL2), macrophage inflammatory protein (MIP) neurotypical controls, with increased levels of sTREM2 and in- 1a (MIP-1a, also known as CCL3), MIP-1b (also known as CCL4), flammatory markers in plasma. In young adults with DS, sTREM2 TNF-a, TNF-b, and vascular endothelial growth factor (VEGF). correlated positively with 24 of the 38 measured cytokines, whereas Statistical analyses there were no significant correlations in the control group. In addition, sTREM2 clustered with different cytokines in the two DS and control demographics were compared using unpaired t test for age and Fisher exact test for APOE4 status and sex distribution. Plasma groups. The results of this preliminary report implicate an al- sTREM2andinflammatorymarkersweremeasuredinplasmaonplates tered relationship between sTREM2 and inflammatory markers that also contained buffer-alone background wells (containing 0 pg/ml of in young adults with DS predementia. each protein) and standard curve wells containing known concentrations of each protein measured. Concentrations of analytes were determined Materials and Methods based on fluorescence of the standard curves for the respective proteins. Concentration values were log10 transformed for comparison.