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

Suárez‐Calvet, Marc; Caballero, Miguel Ángel Araque; Kleinberger, Gernot; Bateman, Randall J.; Fagan, Anne M.; Morris, John C.; Xiong, Chengjie; Danek, Adrian; Ewers, Michael; Haass, Christian

doi:10.1126/scitranslmed.aag1767

Cited by 224 publications

(290 citation statements)

References 69 publications

(115 reference statements)

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“…Therefore, although TREM2 may not have a dramatic effect on the overall Aβ content of the diseased brain, it strongly affects the ability of microglia to respond to and contain the plaques. In support of a role for TREM2 in microgliosis, a recent study found that production of sTREM2 is increased prior to the onset of symptoms but after initial markers of Aβ accumulation and neuronal injury [48]. This sTREM2 continues to increase until after the onset of symptoms and highlights the role for TREM2 in microgliosis at a critical point for the response to accumulating damage from disease.…”

Section: Trem2 In Diseasementioning

confidence: 92%

“…While potential functions for sTREM2 are discussed below, it is notable that several studies have reported a correlation between CSF tau/p-tau levels and sTREM2 [29, 48, 52–54]. Interestingly, in these studies, sTREM2 is more strongly correlated with CSF tau than Aβ.…”

Section: Trem2 In Diseasementioning

confidence: 96%

“…Given the conflicting reports of TREM2 on Aβ burden, it is tempting to speculate that TREM2 is perhaps involved with the taupathy stage of AD progression. However, a recent paper showed that CSF sTREM2 levels follow both changes to Aβ and tau, and peak during early stages of clinical impairment [48]. This finding suggests that sTREM2 is accumulating during microglial activation in response to these events, and does not produce them.…”

Section: Trem2 In Diseasementioning

confidence: 99%

“…Given that sTREM2 is reported to increase both survival and inflammation in cultured microglia [109], it may be necessary to pair sTREM2 with an anti-inflammatory drug to isolate the pro-survival effect. While these possibilities are explored, CSF sTREM2 certainly has potential as a biomarker for microgliosis during AD onset [48]…”

Section: Trem2 Function and Model For Ligand Engagementmentioning

confidence: 99%

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TREM2-Ligand Interactions in Health and Disease

Kober

Brett

2017

Journal of Molecular Biology

172

166

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The protein Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunomodulatory receptor with a central role in myeloid cell activation and survival. In recent years, the importance of TREM2 has been highlighted by the identification of coding variants that increase risk for Alzheimer’s disease and other neurodegenerative diseases. Animal studies have further shown the importance of TREM2 in neurodegenerative and other inflammatory disease models including chronic obstructive pulmonary disease, multiple sclerosis, and stroke. A mechanistic understanding of TREM2 function remains elusive, however, due in part to the absence of conclusive information regarding the identity of endogenous TREM2 ligands. While many TREM2 ligands have been proposed, their physiological role and mechanism of engagement remain to be determined. In this review, we highlight the suggested roles of TREM2 in these diseases, recent advances in our understanding of TREM2, and discuss putative TREM2-ligand interactions and their potential roles in signaling during health and disease. We develop a model based on the TREM2 structure to explain how different TREM2 ligands might interact with the receptor and how disease-risk variants may alter ligand interactions. Finally, we propose future experimental directions to establish the role and importance of these different interactions on TREM2 function.

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Section: Trem2 In Diseasementioning

confidence: 92%

Section: Trem2 In Diseasementioning

confidence: 96%

Section: Trem2 In Diseasementioning

confidence: 99%

Section: Trem2 Function and Model For Ligand Engagementmentioning

confidence: 99%

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TREM2-Ligand Interactions in Health and Disease

Kober

Brett

2017

Journal of Molecular Biology

172

166

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“…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]. The effect of TREM2 genetic variants on CSF sTREM2 [ 5 6 6 _ T D $ D I F F ] do not show a consistent trend; for instance, one report suggests that the R47H variant can increase sTREM2, the T96K[ 5 6 7 _ T D $ D I F F ] /L211P/W191X (these variants were in linkage disequilibrium) variants slightly reduce, while the R62H variant does not seem to change sTREM2 levels compared to wild-type TREM2 carriers [109].…”

Section: Regulation Of Trem2 Gene Expressionmentioning

confidence: 99%

TREM2, Microglia, and Neurodegenerative Diseases

Yeh¹,

Hansen²,

Sheng³

2017

Trends in Molecular Medicine

330

271

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Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

Llibre‐Guerra

Schindler

et al. 2019

JAMA Netw Open

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IMPORTANCE The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. OBJECTIVES To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. MAIN OUTCOMES AND MEASURES Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. RESULTS Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], −0.3 [0.4]) and 10 years (mean [SE], −0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. (continued) Key Points Question How do different proposed measurements of tau brain pathologic abnormalities (ie, levels of phosphorylated tau 181 in the cerebrospinal fluid [CSF]) and neurodegenera...

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

Cited by 224 publications

References 69 publications

TREM2-Ligand Interactions in Health and Disease

TREM2-Ligand Interactions in Health and Disease

TREM2, Microglia, and Neurodegenerative Diseases

Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

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