Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease

Abstract

BackgroundThe 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.FindingsWe 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.ConclusionCSF 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0071-x) contains supplementary material, which is available to authorized users.

CSF progranulin increases in the course of Alzheimer's disease and is associated with sTREM 2, neurodegeneration and cognitive decline

“…Since PGRN is highly increased upon activation of microglia (Petkau et al , ), we speculate that increased CSF PGRN reflects elevated microglial function. It is well established that activation of microglia occurs in AD (Lyman et al , ; Heneka et al , ) and, in fact, we and others have previously shown that CSF sTREM2 also increases throughout the evolution of the disease (Heslegrave et al , ; Piccio et al , ; Suárez‐Calvet et al , ,b). A remarkable finding of this study is that higher CSF PGRN levels are associated with higher CSF sTREM2 levels exclusively when disease occurs (either in ADAD MC, late‐onset AD or in SNAP) but not in controls.…”

“…The levels of CSF PGRN were significantly increased in MC compared to NC ( F 1,210 = 17.6, P = 0.00004, Fig A, ). In contrast to CSF sTREM2 (Henjum et al , ; Heslegrave et al , ; Piccio et al , ; Suárez‐Calvet et al , ,b), CSF PGRN was not significantly associated with age, neither in the entire sample (β = 0.118, P = 0.079), nor when stratifying by mutation status (for NC: β = 0.125, P = 0.283; for MC: β = 0.131, P = 0.142, Fig B). Consistent with previous publications (Nicholson et al , ; Morenas‐Rodríguez et al , ), CSF PGRN was higher in males than in females ( F 1,210 = 6.35, P = 0.012, Fig C) and were not affected by APOE ε4 status ( F 1,210 = 0.041, P = 0.840).…”

“…We and others previously described an increase in the microglial‐derived protein sTREM2 in the CSF of both ADAD and late‐onset AD patients (Heslegrave et al , ; Piccio et al , ; Suárez‐Calvet et al , ,b). Since CSF PGRN also gradually increases during the course of the disease and it is mainly produced by activated microglia (Daniel et al , ; Naphade et al , ; Petkau et al , ; Philips et al , ; Kleinberger et al , ; Suh et al , ), we investigated whether these two proteins are associated (Figs A and B, and A–C).…”

TREM2, Microglia, and Neurodegenerative Diseases

“…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].…”

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].…”