Cerebrospinal fluid soluble TREM2 in aging and Alzheimer’s disease

Abstract

BackgroundAlzheimer’s disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF).MethodsWe developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n = 50).ResultsWe found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p < 0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p < 0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p < 0.001; n = 50) and amyloid-β1–42 (Aβ42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Aβ42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Aβ42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46).ConclusionssTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Aβ42, T-tau or P-tau.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0182-1) contains supplementary material, which is available to authorized users.

TREM2, Microglia, and Neurodegenerative Diseases

“…Of note, sTREM2 levels are higher in males than in females [109]. Compared to healthy controls, CSF levels of sTREM2 have been shown to be elevated in subjects with multiple sclerosis (MS) [111,112], AD [56,[108][109][110], [ 5 6 4 _ T D $ D I F F ] and FTD [109]. By contrast, sTREM2 concentrations in plasma have not been found to be significantly different between AD patients and controls [109].…”

“…In AD patients, there are reports that sTREM2 levels correlate with those of total tau and phospho-tau in CSF, but not with Ab 1-42 levels [108][109][110]113]. Furthermore, studies of subjects with dominantly inherited AD have shown that CSF TREM2 elevation can occur approximately 5 years before onset of symptoms and after [ 5 6 5 _ T D $ D I F F ] an increase in Ab deposition and CSF tau levels [114].…”

“…Under normal conditions, the actual shedding of TREM2 might help to explain why TREM2 protein is not readily detected on adult microglia despite the abundant expression of TREM2 mRNA [51,56]. When considering the potential of sTREM2 as a biomarker for neurodegeneration, it is known that sTREM2 is normally found in human cerebrospinal fluid (CSF) at $0.2-4 ng/ml, and its concentration increases with age [108][109][110]. Of note, sTREM2 levels are higher in males than in females [109].…”

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

“…Whereas CSF sTREM2 is a topic of great interest as a potential marker for neurodegenerative diseases, the pathophysiological significance of serum blood sTREM2 remains unclear. Additionally, the function of sTREM2 has not been elucidated, although elevated sTREM2 levels in CSF have been suggested to reflect microglial activation in response to neuronal degeneration [27][28][29][30][31]. In this respect, recent studies uncovered sTREM2 as not just an inactive end-product but also a signaling molecule [15] that promotes macrophage survival by preventing apoptosis [32] and activates microglia to ultimately trigger inflammatory responses and prolong survival [33].…”

“…TREM2 is assumed to exhibit anti-inflammatory roles, mainly based on in vitro analyses; however, recent growing evidence highlights the pro-inflammatory roles of TREM2 in in vivo disease settings [12] and suggest pathological implications of TREM2-expressing microglia in neuroinflammation and concomitant neurodegeneration, with a shift in microglial phenotypes from homeostasis to disease states. sTREM2 is detected in human blood and cerebrospinal fluid (CSF), and CSF sTREM2 levels are elevated in patients with neurodegenerative diseases compared to healthy controls [18,[26][27][28][29][30]. Whereas CSF sTREM2 is a topic of great interest as a potential marker for neurodegenerative diseases, the pathophysiological significance of serum blood sTREM2 remains unclear.…”