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Cited by 200Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsProtease and Inhibitor Mechanisms

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TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant

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Thornton, Peter, Sevalle, Jean, Deery, Michael J, Fraser, Graham, Zhou, Ye, Ståhl, Sara, Franssen, Elske H, Dodd, Roger B, Qamar, Seema, Gomez Perez‐Nievas, Beatriz, Nicol, Louise SC, Eketjäll, Susanna, Revell, Jefferson, Jones, Clare, Billinton, Andrew, St George‐Hyslop, Peter H, Chessell, Iain, Crowther, Damian C·2017·EMBO Molecular Medicine
DOI 10.15252/emmm.201707673PMC PMC5623839
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Abstract

We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2‐expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N‐terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157‐S158 peptide bond for both wild‐type and H157Y human TREM2 and for the wild‐type murine orthologue. Crucially, we also show that the Alzheimer's disease‐associated H157Y TREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat‐ and ADAM10‐siRNA‐independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases.

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Figure 1 TREM2 expression, glycosylation and proteolysis Surface TREM2 was detected on non‐permeabilised primary human macrophages labelled with anti‐TREM2 polyclonal antiserum (1, red), but not a control antiserum (2) and by live cell immunostaining of HEK293 stably transfected with wild‐type hTREM2 (3, pink; nuclei stained with Hoechst) but not on parental HEK293 (4). Surface immunolocalisation was also observed. Scale bars = 20 μm.Western blots of lysates (L) and supernatants (S) for hTREM2 from parental HEK293 vs. HEK293+hTREM2 cells showed distinct isoforms of TREM2. The cell lysate (HEK293+hTREM2, L) yielded an immature glycoform at 35 kDa with a less intense smear up to 50 kDa. This smear was the predominant species in the supernatant (HEK293+hTREM2, S). Similar distributions of TREM2 were seen in primary human macrophages (Macrophage, L and S).Subcellular fractionation of macrophages over a time course revealed the fate of surface‐biotinylated TREM2 (membrane‐associated in blue circles), indicating that most protein was shed into the supernatant (red squares), with a half time of < 1 h, and that little was found in cytosol or nuclear cellular fractions (green triangles & purple inverted triangles). Data plotted as mean ± SEM; n = 4 replicates. Source data are available online for this figure.
Figure 1 TREM2 expression, glycosylation and proteolysis Surface TREM2 was detected on non‐permeabilised primary human macrophages labelled with anti‐TREM2 polyclonal antiserum (1, red), but not a control antiserum (2) and by live cell immunostaining of HEK293 stably transfected with wild‐type hTREM2 (3, pink; nuclei stained with Hoechst) but not on parental HEK293 (4). Surface immunolocalisation was also observed. Scale bars = 20 μm.Western blots of lysates (L) and supernatants (S) for hTREM2 from parental HEK293 vs. HEK293+hTREM2 cells showed distinct isoforms of TREM2. The cell lysate (HEK293+hTREM2, L) yielded an immature glycoform at 35 kDa with a less intense smear up to 50 kDa. This smear was the predominant species in the supernatant (HEK293+hTREM2, S). Similar distributions of TREM2 were seen in primary human macrophages (Macrophage, L and S).Subcellular fractionation of macrophages over a time course revealed the fate of surface‐biotinylated TREM2 (membrane‐associated in blue circles), indicating that most protein was shed into the supernatant (red squares), with a half time of < 1 h, and that little was found in cytosol or nuclear cellular fractions (green triangles & purple inverted triangles). Data plotted as mean ± SEM; n = 4 replicates. Source data are available online for this figure.CC BY · PubMed Central
Figure EV1 Surface biotinylation and fate of TREM2 Surface‐expressed TREM2 on human macrophages was biotinylated at t = 0 and fractionated into four pools: supernatant, membrane‐associated, cytosolic and nuclear. Similar fractionation was undertaken following incubation for 0.5, 1.0 and 4.5 h. TREM2‐associated biotin was purified by immunoprecipitation and quantified by MSD for biotinylated TREM2. The raw and processed data are presented here. The left block of data shows biotin TREM2 measurements for four timepoints for four biological replicates for each of the four subcellular pools. The right block of data represents the normalised TREM2 quantification, with the membrane fraction at t = 0 defined as 100%.
Figure EV1 Surface biotinylation and fate of TREM2 Surface‐expressed TREM2 on human macrophages was biotinylated at t = 0 and fractionated into four pools: supernatant, membrane‐associated, cytosolic and nuclear. Similar fractionation was undertaken following incubation for 0.5, 1.0 and 4.5 h. TREM2‐associated biotin was purified by immunoprecipitation and quantified by MSD for biotinylated TREM2. The raw and processed data are presented here. The left block of data shows biotin TREM2 measurements for four timepoints for four biological replicates for each of the four subcellular pools. The right block of data represents the normalised TREM2 quantification, with the membrane fraction at t = 0 defined as 100%.CC BY · PubMed Central
Figure 2 Shedding of glycosylated TREM2 NTF is sensitive to inhibitors of ADAM10 and matrix metalloproteinases Western blotting of the conditioned media from primary murine microglia (left panel), transfected HEK293 cells (middle panel) and primary human macrophages (right panel) revealed the presence of shed wild‐type TREM2. This soluble TREM2 appeared as a > 35 kDa smear of various glycoforms and upon deglycosylation was reduced to a single band of 17 kDa (arrowhead). The ADAM10 inhibitor, GI254023X, blocked shedding in transfected HEK293 cell and macrophage cultures.The concentration of shed TREM2 in the supernatant of macrophage cultures was reduced to ˜50% by 20 μM of both GI254023X and the broad‐spectrum metalloprotease inhibitor GM6001, as measured by an MSD assay. By contrast, the broad‐spectrum serine protease inhibitor PMSF did not reduce shedding. Experiments were repeated three times and for two donors of the macrophage progenitors. Data plotted as mean ± SEM.In HEK293 cells, GI254023X and GM6001 had comparable potencies; however, the MMP2/9 inhibitor SB‐3CT did not block shedding. Data plotted as mean ± SEM; n = 3 replicates. Source data are available online for this figure.
Figure 2 Shedding of glycosylated TREM2 NTF is sensitive to inhibitors of ADAM10 and matrix metalloproteinases Western blotting of the conditioned media from primary murine microglia (left panel), transfected HEK293 cells (middle panel) and primary human macrophages (right panel) revealed the presence of shed wild‐type TREM2. This soluble TREM2 appeared as a > 35 kDa smear of various glycoforms and upon deglycosylation was reduced to a single band of 17 kDa (arrowhead). The ADAM10 inhibitor, GI254023X, blocked shedding in transfected HEK293 cell and macrophage cultures.The concentration of shed TREM2 in the supernatant of macrophage cultures was reduced to ˜50% by 20 μM of both GI254023X and the broad‐spectrum metalloprotease inhibitor GM6001, as measured by an MSD assay. By contrast, the broad‐spectrum serine protease inhibitor PMSF did not reduce shedding. Experiments were repeated three times and for two donors of the macrophage progenitors. Data plotted as mean ± SEM.In HEK293 cells, GI254023X and GM6001 had comparable potencies; however, the MMP2/9 inhibitor SB‐3CT did not block shedding. Data plotted as mean ± SEM; n = 3 replicates. Source data are available online for this figure.CC BY · PubMed Central
Figure 3 Peptidomimetic protease inhibitors point to residues 158–160 as the site of sheddase cleavage An overlapping library of retro‐inverso peptides were designed to mimic the extracellular peri‐membranous domain of TREM2 in the region of the sheddase site (TM: transmembrane). Blue boxes represent retro‐inverso peptides that reduce TREM2 shedding; red boxes those that do not. The black box indicates the three residues that are common to all the inhibitory retro‐inverso peptides.The peptidomimetics were incubated with primary human macrophages, and the resulting levels of shed TREM2 NTF were quantified by MSD ELISA. Blue = inhibitory; red = non‐inhibitory. Values plotted: mean ± SEM; each experiment was repeated for 3–5 independent human donors.Peptides including amino acids 158–160 (blue) inhibited TREM2 shedding more than retro‐inverso peptides that did not (red). Values plotted: mean ± SEM; two‐tailed Student's t‐test, ***P = 0.003; each experiment was repeated for 3–5 independent human donors.Forward and reverse TREM2 peptidomimetics containing residues 158–160 suppressed TREM2 shedding equally. Values plotted: mean ± SEM; n = 3 replicates; two‐tailed Student's t‐test; ns = not significant.
Figure 3 Peptidomimetic protease inhibitors point to residues 158–160 as the site of sheddase cleavage An overlapping library of retro‐inverso peptides were designed to mimic the extracellular peri‐membranous domain of TREM2 in the region of the sheddase site (TM: transmembrane). Blue boxes represent retro‐inverso peptides that reduce TREM2 shedding; red boxes those that do not. The black box indicates the three residues that are common to all the inhibitory retro‐inverso peptides.The peptidomimetics were incubated with primary human macrophages, and the resulting levels of shed TREM2 NTF were quantified by MSD ELISA. Blue = inhibitory; red = non‐inhibitory. Values plotted: mean ± SEM; each experiment was repeated for 3–5 independent human donors.Peptides including amino acids 158–160 (blue) inhibited TREM2 shedding more than retro‐inverso peptides that did not (red). Values plotted: mean ± SEM; two‐tailed Student's t‐test, ***P = 0.003; each experiment was repeated for 3–5 independent human donors.Forward and reverse TREM2 peptidomimetics containing residues 158–160 suppressed TREM2 shedding equally. Values plotted: mean ± SEM; n = 3 replicates; two‐tailed Student's t‐test; ns = not significant.CC BY · PubMed Central
Figure 4 Mass spectrometry identifies His157‐Ser158 as the sheddase site TREM2 was immunoprecipitated and deglycosylated from primary human macrophage conditioned media. Two specific bands were visible on a silver‐stained SDS–PAGE gel (arrowheads 1 & 2). These bands were excised, digested with trypsin and analysed by LC‐MS/MS.TREM2 in the conditioned media of primary human macrophages (black), primary murine microglia (white) and HEK293 cells stably expressing hTREM2 (grey) was digested with trypsin and the resulting peptides identified by mass spectrometry. The most frequent C‐terminal residue not consistent with trypsin digestion was H157 (from two donors/biological replicates of HEK293 cells; each replicate assayed in separate mass spectrometry laboratories; n = total number of peptides identified; where peptide sequences differ between species they are shown as human/mouse).Trypsin digestion (red sites) of band 1 provided almost complete coverage of macrophage TREM2 (bold), lacking only the peptide expected to have R52 at its C‐terminus. Non‐trypsin cleavage (blue) was observed predominantly at H157. The absence of the peptide with K42 at its C‐terminus suggests that N‐terminal truncation is responsible for generating band 2. Underlined: predicted secretion signal peptide.Peptides from the supernatants of HEK293 cells transiently expressing wild‐type (black) and H157Y (white) human TREM2, and co‐expressing human DAP12, were identified by mass spectrometry. The most common C‐terminus was residue 157 for both TREM2 isoforms (one biological replicate; n = total number of peptides identified; where WT and variant sequences vary they are shown as WT/variant).Schematic of the TREM2 protein. SP, signal peptide; IG domain, immunoglobulin domain; TM, transmembrane domain; triangles, N‐glycosylation sites; arrow, site of proteolytic shedding; all numbers relate to amino acid positions. Source data are available online for this figure.
Figure 4 Mass spectrometry identifies His157‐Ser158 as the sheddase site TREM2 was immunoprecipitated and deglycosylated from primary human macrophage conditioned media. Two specific bands were visible on a silver‐stained SDS–PAGE gel (arrowheads 1 & 2). These bands were excised, digested with trypsin and analysed by LC‐MS/MS.TREM2 in the conditioned media of primary human macrophages (black), primary murine microglia (white) and HEK293 cells stably expressing hTREM2 (grey) was digested with trypsin and the resulting peptides identified by mass spectrometry. The most frequent C‐terminal residue not consistent with trypsin digestion was H157 (from two donors/biological replicates of HEK293 cells; each replicate assayed in separate mass spectrometry laboratories; n = total number of peptides identified; where peptide sequences differ between species they are shown as human/mouse).Trypsin digestion (red sites) of band 1 provided almost complete coverage of macrophage TREM2 (bold), lacking only the peptide expected to have R52 at its C‐terminus. Non‐trypsin cleavage (blue) was observed predominantly at H157. The absence of the peptide with K42 at its C‐terminus suggests that N‐terminal truncation is responsible for generating band 2. Underlined: predicted secretion signal peptide.Peptides from the supernatants of HEK293 cells transiently expressing wild‐type (black) and H157Y (white) human TREM2, and co‐expressing human DAP12, were identified by mass spectrometry. The most common C‐terminus was residue 157 for both TREM2 isoforms (one biological replicate; n = total number of peptides identified; where WT and variant sequences vary they are shown as WT/variant).Schematic of the TREM2 protein. SP, signal peptide; IG domain, immunoglobulin domain; TM, transmembrane domain; triangles, N‐glycosylation sites; arrow, site of proteolytic shedding; all numbers relate to amino acid positions. Source data are available online for this figure.CC BY · PubMed Central
Figure 5 The disease‐linked H157Y variant of TREM2 is shed more rapidly than wild‐type TREM2 Western blot for TREM2 in lysates of HEK293 cells transiently expressing either wild‐type (WT) or the H157Y variant protein (N = 3): levels of immature TREM2 (major band at 35 kDa) were unchanged by the H157Y substitution; however, total levels of the variant were reduced as compared to WT because of a more marked reduction in the levels of the glycosylated isoform. The proteolytic cleavage of TREM2 generated a truncated C‐terminal fragment (CTF) that was more abundant in lysates from cells expressing H157Y TREM2. GAPDH was the loading control; DAP12 was co‐expressed with TREM2. Molecular mass markers in kDa.Quantitation of the full‐length TREM2 isoforms as shown in panel (A) (data plotted as mean ± SEM; N = 12).Western blot for the shed TREM2 NTF from the conditioned medium of HEK293 cell cultures (N = 3): levels of H157Y TREM2 NTF were higher than WT. A secreted fragment of the amyloid precursor protein (sAPPa) was the loading control. Molecular mass markers in kDa.The proteolytic fragments of TREM2 as shown in panel (A) (CTF, N = 3) and panel (C) (NTF, N = 15) were corrected for the total full‐length TREM2 (FL) from each cell lysate: the levels of the shed N‐terminal fragment (NTF) of TREM2 were higher in cells expressing the H157Y variant as compared to WT. Data plotted as mean ± SEM.Western blot for TREM2 from the conditioned medium of HEK293 cell cultures treated with varying concentrations of either GI254023X or batimastat (bat): inhibition of TREM2 NTF shedding by GI254023X was equivalent for both variant and WT TREM2; however, more shedding was observed at the higher concentration of batimastat for H157Y TREM2 as compared to WT. Molecular mass markers in kDa.Quantification of total TREM2 shed from HEK293 cells as shown in panel (E) (N = 7). Maximal concentrations of GI254023X blocked shedding equally for WT and variant TREM2. Batimastat‐resistant shedding was more marked for H157Y TREM2. Data plotted as mean ± SEM.Schematic showing the proteolytic enzymes expected to be active in the presence of the protease inhibitors used in (E and F). MMP: matrix metalloproteinase.Data information: Concentration of inhibitors in micromolar. Two‐tailed Student's t‐test, P‐values: *P < 0.05; ***P < 0.001.Source data are available online for this figure.
Figure 5 The disease‐linked H157Y variant of TREM2 is shed more rapidly than wild‐type TREM2 Western blot for TREM2 in lysates of HEK293 cells transiently expressing either wild‐type (WT) or the H157Y variant protein (N = 3): levels of immature TREM2 (major band at 35 kDa) were unchanged by the H157Y substitution; however, total levels of the variant were reduced as compared to WT because of a more marked reduction in the levels of the glycosylated isoform. The proteolytic cleavage of TREM2 generated a truncated C‐terminal fragment (CTF) that was more abundant in lysates from cells expressing H157Y TREM2. GAPDH was the loading control; DAP12 was co‐expressed with TREM2. Molecular mass markers in kDa.Quantitation of the full‐length TREM2 isoforms as shown in panel (A) (data plotted as mean ± SEM; N = 12).Western blot for the shed TREM2 NTF from the conditioned medium of HEK293 cell cultures (N = 3): levels of H157Y TREM2 NTF were higher than WT. A secreted fragment of the amyloid precursor protein (sAPPa) was the loading control. Molecular mass markers in kDa.The proteolytic fragments of TREM2 as shown in panel (A) (CTF, N = 3) and panel (C) (NTF, N = 15) were corrected for the total full‐length TREM2 (FL) from each cell lysate: the levels of the shed N‐terminal fragment (NTF) of TREM2 were higher in cells expressing the H157Y variant as compared to WT. Data plotted as mean ± SEM.Western blot for TREM2 from the conditioned medium of HEK293 cell cultures treated with varying concentrations of either GI254023X or batimastat (bat): inhibition of TREM2 NTF shedding by GI254023X was equivalent for both variant and WT TREM2; however, more shedding was observed at the higher concentration of batimastat for H157Y TREM2 as compared to WT. Molecular mass markers in kDa.Quantification of total TREM2 shed from HEK293 cells as shown in panel (E) (N = 7). Maximal concentrations of GI254023X blocked shedding equally for WT and variant TREM2. Batimastat‐resistant shedding was more marked for H157Y TREM2. Data plotted as mean ± SEM.Schematic showing the proteolytic enzymes expected to be active in the presence of the protease inhibitors used in (E and F). MMP: matrix metalloproteinase.Data information: Concentration of inhibitors in micromolar. Two‐tailed Student's t‐test, P‐values: *P < 0.05; ***P < 0.001.Source data are available online for this figure.CC BY · PubMed Central
Figure EV2 Titration of batimastat against WT and H157Y TREM2 shedding The concentration of batimastat in the culture medium of HEK293 cells expressing either WT or H157Y TREM2 (with hDAP12) was varied over 4.5 orders of magnitude and shed TREM2 quantified bt MSD assay 24 h later. More batimastat‐resistant shedding of the variant TREM2 is apparent at higher inhibitor concentrations as compared to the WT protein. Data plotted as mean ± SEM.
Figure EV2 Titration of batimastat against WT and H157Y TREM2 shedding The concentration of batimastat in the culture medium of HEK293 cells expressing either WT or H157Y TREM2 (with hDAP12) was varied over 4.5 orders of magnitude and shed TREM2 quantified bt MSD assay 24 h later. More batimastat‐resistant shedding of the variant TREM2 is apparent at higher inhibitor concentrations as compared to the WT protein. Data plotted as mean ± SEM.CC BY · PubMed Central
Figure EV3 The disease‐linked H157Y variant of TREM2 is shed more rapidly from the cell surface A–E(A) Western blot of HEK293‐HaloTag‐hTREM2 cells demonstrating full‐length protein (FL) and also levels of the TREM2 C‐terminal fragment (CTF) that were higher for the H157Y variant (H157Y) as compared to wild type, particularly at 24 h (quantified in C). (B) Likewise, the NTF from the same cells accumulated more in the H157Y variant‐expressing cell supernatants (quantified in D). (E) Levels of DAP12, expressed from the same plasmid, were unchanged.F, GInhibition of shedding by GI254023X was equivalent for both isoforms of TREM2 (F); however, the metalloprotease inhibitor batimastat (G) was less effective at blocking shedding of the H157Y variant.Data information: Data plotted as mean ± SEM. Two‐tailed Student's t‐test. Source data are available online for this figure.
Figure EV3 The disease‐linked H157Y variant of TREM2 is shed more rapidly from the cell surface A–E(A) Western blot of HEK293‐HaloTag‐hTREM2 cells demonstrating full‐length protein (FL) and also levels of the TREM2 C‐terminal fragment (CTF) that were higher for the H157Y variant (H157Y) as compared to wild type, particularly at 24 h (quantified in C). (B) Likewise, the NTF from the same cells accumulated more in the H157Y variant‐expressing cell supernatants (quantified in D). (E) Levels of DAP12, expressed from the same plasmid, were unchanged.F, GInhibition of shedding by GI254023X was equivalent for both isoforms of TREM2 (F); however, the metalloprotease inhibitor batimastat (G) was less effective at blocking shedding of the H157Y variant.Data information: Data plotted as mean ± SEM. Two‐tailed Student's t‐test. Source data are available online for this figure.CC BY · PubMed Central
Figure 6 Knock‐down of ADAM10 is less effective at reducing the shedding of H157Y TREM2 A, BWestern blot of HEK293 cells for ADAM10 (A) or ADAM17 and reprobed for β‐actin (B) confirmed siRNA‐mediated knock‐down of target proteins (arrowheads). siRNA pools, or vehicle, added to cells as indicated. β‐actin (asterisk) was the loading control.CQuantitation of WT and H157Y (SEM error bars) TREM2 NTF in the conditioned media of HEK293 cells as compared to untreated cells measured by MSD assay (N = 8): ADAM10 siRNA reduced shedding whether applied alone or in combination with ADAM17 siRNA. ADAM17 siRNA was ineffective. Fractional inhibition of shedding was greatest for WT TREM2 using ADAM10 siRNA. Source data are available online for this figure.
Figure 6 Knock‐down of ADAM10 is less effective at reducing the shedding of H157Y TREM2 A, BWestern blot of HEK293 cells for ADAM10 (A) or ADAM17 and reprobed for β‐actin (B) confirmed siRNA‐mediated knock‐down of target proteins (arrowheads). siRNA pools, or vehicle, added to cells as indicated. β‐actin (asterisk) was the loading control.CQuantitation of WT and H157Y (SEM error bars) TREM2 NTF in the conditioned media of HEK293 cells as compared to untreated cells measured by MSD assay (N = 8): ADAM10 siRNA reduced shedding whether applied alone or in combination with ADAM17 siRNA. ADAM17 siRNA was ineffective. Fractional inhibition of shedding was greatest for WT TREM2 using ADAM10 siRNA. Source data are available online for this figure.CC BY · PubMed Central
Figure EV4 Validation data for the shed TREM2 MSD assay A, BThe MSD assay detected TREM2 in the conditioned media (A) and lysates (B) of HEK293 cells stably expressing hTREM2 and of primary human macrophages but not in parental HEK293 cultures. ND = not detected.
Figure EV4 Validation data for the shed TREM2 MSD assay A, BThe MSD assay detected TREM2 in the conditioned media (A) and lysates (B) of HEK293 cells stably expressing hTREM2 and of primary human macrophages but not in parental HEK293 cultures. ND = not detected.CC BY · PubMed Central

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  1. Jonsson T, Stefansson K (2013) TREM2 and neurodegenerative disease. N Engl J Med 369: 1568–1569

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Metadata

Authors
Thornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez‐Nievas, B., Nicol, L. S., Eketjäll, S., Revell, J., Jones, C., Billinton, A., St George‐Hyslop, P. H., Chessell, I., & Crowther, D. C.
Affiliations
  • AstraZeneca (United Kingdom) (GB)
  • University of Cambridge (GB)
  • University of Toronto (CA)
  • Karolinska Institutet (SE)
  • Integrated Cardio Metabolic Centre (SE)
Corresponding author
Crowther, Damian C
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2017-08-30
Volume
9
Issue
10
Pages
1366-1378
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.201707673
PMC
PMC5623839
OpenAlex
W2753509052
Cited by
200
References
33
Citations by year
2026: 29 · 2025: 34 · 2024: 18 · 2023: 37 · 2022: 17 · 2021: 18 · 2020: 16 · 2019: 14 · 2018: 15 · 2017: 2
FWCI
6.40
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome
  • Canadian Institute of Health Research
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
TREM2, Alzheimer's disease, protein shedding, proteolytic cleavage, ADAM10, metalloproteinase inhibitors, microglia, macrophages, innate immune response, therapeutic target
MeSH terms
ADAM10 Protein, ADAM17 Protein, Alzheimer Disease, Animals, Animals, Newborn, Humans, Ketocholesterols, Macrophages, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred C57BL, Receptors, Immunologic, Culture Media, Conditioned, Microglia, RNA, Small Interfering, Mice, Amyloid Precursor Protein Secretases, HEK293 Cells, Proteolysis, Primary Cell Culture, Matrix Metalloproteinase Inhibitors

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