An Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome: A Preliminary Report

Abstract

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. 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 cerebrospinal 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 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 Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway

“…In addition, observation of changing sTREM2 levels in various contexts of neurodegeneration in humans further highlights the importance of TREM2 in human neurological disease and the exciting possibility of therapeutically targeting TREM2. sTREM2 sTREM2 is detected in human cerebrospinal fluid (CSF), and its levels are elevated in CSF of patients with various neurological conditions, such as MS, AD, Parkinson's disease (PD), frontotemporal dementia (FTD) associated with progranulin (GRN) mutations, natural aging in cognitively unimpaired individuals, and in the plasma of Down syndrome patients (Falcon et al, 2019;Heslegrave et al, 2016;Piccio et al, 2008Piccio et al, , 2016Suá rez-Calvet et al, 2016a, 2016bWeber et al, 2020;Woollacott et al, 2018). Matching CSF concentrations of sTREM2 with other measures of human brain function revealed that sTREM2 corresponds to a genetic AD risk status (Deming et al, 2019;Piccio et al, 2016;Suá rez-Calvet et al, 2016a and correlates with disease hallmarks: total tau and phospho-tau181P levels in CSF in AD patients and total tau in PD patients (Heslegrave et al, 2016;Wilson et al, 2020).…”

TREM2 alters the phagocytic, apoptotic and inflammatory response to Aβ42in HMC3 cells

“…However, these pro-inflammatory effects were significantly attenuated by TREM2 overexpression, while enhanced by TREM2 silencing. (Li et al 2019) The cleaved soluble TREM2 isoform has been associated with alterations in the immune response in Down syndrome (Weber et al 2020), after exercise (Jensen et al 2019), and AD. (Bekris et al 2018, Brosseron et al 2018, Rauchmann et al 2020) Interestingly, CSF sTREM2 was positively associated with the pro-inflammatory proteins and anti-inflammatory proteins.…”

The relationship of soluble TREM2 to other biomarkers of sporadic Alzheimer’s disease

“…The opposite results were reported in a study performed on AD and healthy subjects, where increased levels of CSF sTREM2 were observed in AD patients, particularly in the early stage; however, plasma levels were not different between the two groups, suggesting incorrect plasma sTREM2 levels 11 , 39 . In AD, the plasma sTREM2 levels may not necessarily reflect the CSF sTREM2 levels, and may not follow the same dynamics as CSF sTREM2 33 , 40 . Further studies are required to clarify this.…”