Morenas-Rodríguez E, Li Y, Nuscher B, Franzmeier N, Xiong C, Suárez-Calvet M, Fagan AM, Schultz S, Gordon BA, Benzinger TL, Hassenstab J, McDade E, Feederle R, Karch CM, Schlepckow K, Morris JC, Kleinberger G, Nellgard B, Vöglein J, Blennow K, Zetterberg H, Ewers M, Jucker M, Levin J, Bateman RJ, Haass C, Dominantly Inherited Alzheimer Network. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol. 2022 Apr;21(4):329-341. PubMed.

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  1. TREM2 is a cell surface receptor of the immunoglobulin superfamily that is expressed exclusively in the myeloid lineage cells, particularly microglia in the central nervous system. Engagement of TREM2 by ligands, such as lipoproteins or Aβ, initiates signaling through its adaptors DAP12 or DAP10 to trigger downstream signaling pathways. Importantly, TREM2 signaling is required for the sequential activation of microglia from a homeostatic to a disease-associated state in response to Aβ plaques. TREM2 also undergoes regulated proteolytic cleavage by ADAM10 and ADAM17 at the H157–S158 peptide bond, generating soluble TREM2 (sTREM2). We have reported previously that sTREM2 plays important roles in enhancing microglial functions such as proliferation, migration, survival, clustering around amyloid plaques, and the uptake and degradation of Aβ (Zhong et al., 2019), suggesting a beneficial role of sTREM2 against Aβ pathology.

    In this paper, Christian Haass and colleagues performed longitudinal analysis of CSF sTREM2 among patients from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes presymptomatic and symptomatic AD patients. They found that the increase in CSF sTREM2 is correlated with diminished brain Aβ deposition, decreased cortical shrinkage in the precuneus, and diminished cognitive decline, whereas slower sTREM2 increase corelates with enhanced CSF p-tau and a boost in brain Aβ deposition.

    These findings support a critical role of TREM2-mediated microglial response during AD, suggesting that sTREM2 can be a key biomarker for predicting AD-related outcomes in the early stages of the disease.

    Although sTREM2 is abundant in CSF and its level negatively correlates with Aβ deposition, it is still unclear how CSF sTREM2 relates to TREM2 signaling and microglial functions and phenotypes in the brain. Could shedding of TREM2 to generate sTREM2 be a regulated response to pathogenic stimuli, allowing sTREM2 to work in harmony with cell surface TREM2 to provide stronger protection against Aβ pathology and related toxicity?

    In a Phase I study of the TREM2 agonist antibody AL002 (Wang et al., 2020), a dose-dependent decrease in CSF sTREM2 from baseline within two days was observed. This indicates that boosting TREM2 signaling may reduce the proteolytic shedding of TREM2. As such, whether a reduction of sTREM2 in the brain contributes to the beneficial effect of this TREM2 antibody remains unclear.

    Further investigation on the relationships and regulation among TREM2 signaling, sTREM2, and microglia activation in the context of Aβ should be conducted to guide mechanism-based design of AD clinical trials targeting TREM2 or sTREM2. Additionally, as single nuclei RNA-Seq of selected brains from these DIAN studies has been obtained (Brase et al., 2021), it will be very interesting and informative to analyze the correlation between CSF sTREM2 and the microglial transcriptional profiles in the same brains, to further understand the link between CSF sTREM2 as biomarker and the microglia function.

    References:

    Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, Wang D, Gao Y, Zhu Y, Sheng X, Chen K, Wang N, Zhu L, Can D, Marten Y, Shinohara M, Liu CC, Du D, Sun H, Wen L, Xu H, Bu G, Chen XF. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model. Nat Commun. 2019 Mar 25;10(1):1365. PubMed.

    Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, Colonna M. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020 Sep 7;217(9) PubMed.

    Brase L, You SF, del Aguila J, Dai Y, Novotny BC, Soriano-Tarraga C, Dykstra T, Fernandez MV, Budde JP, Bergmann K, Morris JC, Bateman RJ, Perrin RJ, McDade E, Xiong C, Goate A, Farlow M, Chhatwal JP, Schofield P, Chui H, Dominantly Inherited Alzheimer Network (DIAN), Sutherland GT, Kipnis J, Karch CM, Benitez BA, Cruchaga C, Harari O. A landscape of the genetic and cellular heterogeneity in Alzheimer disease. medRxiv 2021.11.30. medRxiv

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  2. In this fascinating work from the Haass group, a longitudinal analysis links higher levels of sTREM2 in CSF to apparent slowing of neurodegeneration. This mirrors our own work in amyotrophic lateral sclerosis, where we showed that higher levels of CSF sTREM2 in late disease correlated with prolonged survival (Cooper-Knock et al., 2017). Our work was discussed in a previous Alzforum news piece.

    This supports the idea that a TREM2-mediated microglial response is protective, and that sTREM2 in CSF is a potential biomarker, for multiple neurodegenerative diseases.

    References:

    Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor B, Kirby J, Shaw PJ, Hide W. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2017 Mar 16;5(1):23. PubMed.

    View all comments by Winston Hide

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