sTREM 2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers

Abstract

TREM2 is an innate immune receptor expressed on the surface of microglia. Loss‐of‐function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type‐1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross‐sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non‐AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho‐tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.

Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury

“…Third, the detection of markers in any study, not only in the one described here, depends on the relative sensitivity of the technique used to detect differences, which may not be equal between different markers (42). In regard to the sensitivity of sTREM2 detection, we have shown previously the potential of our ELISA assay to sensitively detect even minor changes in sTREM2 (32, 37). Fourth, ADAD and sporadic AD are different entities.…”

“…However, both share major pathophysiological similarities, and both appear to be triggered by the amyloid cascade (43). Fifth, as we previously stated (32, 37), the overlapping values of CSF sTREM2 levels between patients and controls preclude its use as a diagnostic marker, but it provides a marker to track microglial activity throughout the evolution of the disease. Finally, the results presented here need to be confirmed with an independent microglia-related marker (for example, PET tracer 18 F-GE180, a ligand of the 18-kDa translocator protein TSPO and a marker of activated microglia) (44, 45).…”

“…Consistent with its retention within the ER, sTREM2 is almost undetectable in the CSF and plasma of patients carrying the homozygous p.T66M TREM2 mutation (32, 38). Moreover, we recently demonstrated that the levels of CSF sTREM2 dynamically change during normal aging and during the progression of sporadic AD, where they peak at the early symptomatic stages of the disease (37). …”

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

“…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.…”

“…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].…”