The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
Open accessAbstract
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of TREM2. TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C-terminal to histidine 157, a position where an AD-associated coding variant has been discovered (p.H157Y) in the Han Chinese population. Opposite to the characterized mutations within the Ig-like domain, such as p.T66M and p.Y38C, the p.H157Y variant within the stalk region leads to enhanced shedding of TREM2. Elevated ectodomain shedding reduces cell surface full-length TREM2 and lowers TREM2-dependent phagocytosis. Therefore, two seemingly opposite cellular effects of TREM2 variants, namely reduced versus enhanced shedding, result in similar phenotypic outcomes by reducing cell surface TREM2.
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Cites
TREM2 Variants in Alzheimer's Disease
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Self-citationYeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016) · Neuron · doi:10.1016/j.neuron.2016.06.015 · Cited by 943
Release of Excess Amyloid β Protein from a Mutant Amyloid β Protein Precursor
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TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
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TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
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“Although initially discrepant results regarding the effects of a loss of TREM2 function on amyloid plaque pathology were reported (Jay et al, 2015; Wang et al, 2015), TREM2 loss of function may lead to the accumulation of fuzzy amyloid plaques suggesting a lack of phagocytic clearance of the plaque…”
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Self-citationApolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
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Cited by
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
TREM2 — a key player in microglial biology and Alzheimer disease
Ulland, T. K., & Colonna, M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0072-1 · Cited by 735
The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway
Deczkowska, A., Weiner, A., & Amit, I. (2020) · Cell · doi:10.1016/j.cell.2020.05.003 · Cited by 648
Wang, S., Mustafa, M., Yuede, C. M., Salazar, S. V., Kong, P., Long, H., Ward, M., Siddiqui, O., Paul, R., Gilfillan, S., et al. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20200785 · Cited by 549
Schwartzentruber, J., Cooper, S., Liu, J. Z., Barrio-Hernandez, I., Bello, E., Kumasaka, N., Young, A. M. H., Franklin, R. J. M., Johnson, T., Estrada, K., et al. (2021) · Nature Genetics · doi:10.1038/s41588-020-00776-w · Cited by 532
Metadata
- Authors
- Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., & Haass, C.
- Venue
- EMBO Molecular Medicine
- Published
- 2017-08-30
- Volume
- 9
- Issue
- 10
- Pages
- 1356-1365
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- OpenAlex
- W2752344732
- Cited by
- 261
- References
- 24
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- gold
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- Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., & Haass, C. (2017). An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Molecular Medicine. https://doi.org/10.15252/emmm.201707672
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