Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease

Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Benoit Melchior [verfasserIn] Angie E Garcia [verfasserIn] Bor-Kai Hsiung [verfasserIn] Katherine M Lo [verfasserIn] Jonathan M Doose [verfasserIn] J Cameron Thrash [verfasserIn] Anna K Stalder [verfasserIn] Matthias Staufenbiel [verfasserIn] Harald Neumann [verfasserIn] Monica J Carson [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2010

Übergeordnetes Werk:	In: ASN Neuro - SAGE Publishing, 2009, 2(2010)
Übergeordnetes Werk:	volume:2 ; year:2010

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1042/AN20100010

Katalog-ID:	DOAJ069793697

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allfields	10.1042/AN20100010 doi (DE-627)DOAJ069793697 (DE-599)DOAJ82d86abdff8f47fb87f24b4052f5cd1e DE-627 ger DE-627 rakwb eng RC321-571 Benoit Melchior verfasserin aut Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease 2010 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies. Neurosciences. Biological psychiatry. Neuropsychiatry Angie E Garcia verfasserin aut Bor-Kai Hsiung verfasserin aut Katherine M Lo verfasserin aut Jonathan M Doose verfasserin aut J Cameron Thrash verfasserin aut Anna K Stalder verfasserin aut Matthias Staufenbiel verfasserin aut Harald Neumann verfasserin aut Monica J Carson verfasserin aut In ASN Neuro SAGE Publishing, 2009 2(2010) (DE-627)594772664 (DE-600)2485467-0 17590914 nnns volume:2 year:2010 https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/article/82d86abdff8f47fb87f24b4052f5cd1e kostenfrei https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/toc/1759-0914 Journal toc kostenfrei https://doaj.org/toc/1759-9091 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2 2010
spelling	10.1042/AN20100010 doi (DE-627)DOAJ069793697 (DE-599)DOAJ82d86abdff8f47fb87f24b4052f5cd1e DE-627 ger DE-627 rakwb eng RC321-571 Benoit Melchior verfasserin aut Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease 2010 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies. Neurosciences. Biological psychiatry. Neuropsychiatry Angie E Garcia verfasserin aut Bor-Kai Hsiung verfasserin aut Katherine M Lo verfasserin aut Jonathan M Doose verfasserin aut J Cameron Thrash verfasserin aut Anna K Stalder verfasserin aut Matthias Staufenbiel verfasserin aut Harald Neumann verfasserin aut Monica J Carson verfasserin aut In ASN Neuro SAGE Publishing, 2009 2(2010) (DE-627)594772664 (DE-600)2485467-0 17590914 nnns volume:2 year:2010 https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/article/82d86abdff8f47fb87f24b4052f5cd1e kostenfrei https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/toc/1759-0914 Journal toc kostenfrei https://doaj.org/toc/1759-9091 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2 2010
allfields_unstemmed	10.1042/AN20100010 doi (DE-627)DOAJ069793697 (DE-599)DOAJ82d86abdff8f47fb87f24b4052f5cd1e DE-627 ger DE-627 rakwb eng RC321-571 Benoit Melchior verfasserin aut Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease 2010 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies. Neurosciences. Biological psychiatry. Neuropsychiatry Angie E Garcia verfasserin aut Bor-Kai Hsiung verfasserin aut Katherine M Lo verfasserin aut Jonathan M Doose verfasserin aut J Cameron Thrash verfasserin aut Anna K Stalder verfasserin aut Matthias Staufenbiel verfasserin aut Harald Neumann verfasserin aut Monica J Carson verfasserin aut In ASN Neuro SAGE Publishing, 2009 2(2010) (DE-627)594772664 (DE-600)2485467-0 17590914 nnns volume:2 year:2010 https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/article/82d86abdff8f47fb87f24b4052f5cd1e kostenfrei https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/toc/1759-0914 Journal toc kostenfrei https://doaj.org/toc/1759-9091 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2 2010
allfieldsGer	10.1042/AN20100010 doi (DE-627)DOAJ069793697 (DE-599)DOAJ82d86abdff8f47fb87f24b4052f5cd1e DE-627 ger DE-627 rakwb eng RC321-571 Benoit Melchior verfasserin aut Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease 2010 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies. Neurosciences. Biological psychiatry. Neuropsychiatry Angie E Garcia verfasserin aut Bor-Kai Hsiung verfasserin aut Katherine M Lo verfasserin aut Jonathan M Doose verfasserin aut J Cameron Thrash verfasserin aut Anna K Stalder verfasserin aut Matthias Staufenbiel verfasserin aut Harald Neumann verfasserin aut Monica J Carson verfasserin aut In ASN Neuro SAGE Publishing, 2009 2(2010) (DE-627)594772664 (DE-600)2485467-0 17590914 nnns volume:2 year:2010 https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/article/82d86abdff8f47fb87f24b4052f5cd1e kostenfrei https://doi.org/10.1042/AN20100010 kostenfrei https://doaj.org/toc/1759-0914 Journal toc kostenfrei https://doaj.org/toc/1759-9091 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 2 2010
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title	Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease
ctrlnum	(DE-627)DOAJ069793697 (DE-599)DOAJ82d86abdff8f47fb87f24b4052f5cd1e
title_full	Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease
author_sort	Benoit Melchior
journal	ASN Neuro
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author_browse	Benoit Melchior Angie E Garcia Bor-Kai Hsiung Katherine M Lo Jonathan M Doose J Cameron Thrash Anna K Stalder Matthias Staufenbiel Harald Neumann Monica J Carson
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author-letter	Benoit Melchior
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title_sort	dual induction of trem2 and tolerance-related transcript, tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for alzheimer's disease
callnumber	RC321-571
title_auth	Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease
abstract	Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies.
abstractGer	Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies.
abstract_unstemmed	Vaccine-based autoimmune (anti-amyloid) treatments are currently being examined for their therapeutic potential in Alzheimer's disease. In the present study we examined, in a transgenic model of amyloid pathology, the expression of two molecules previously implicated in decreasing the severity of autoimmune responses: TREM2 (triggering receptor expressed on myeloid cells 2) and the intracellular tolerance-associated transcript, Tmem176b (transmembrane domain protein 176b). In situ hybridization analysis revealed that both molecules were highly expressed in plaque-associated microglia, but their expression defined two different zones of plaque-associated activation. Tmem176b expression was highest in the inner zone of amyloid plaques, whereas TREM2 expression was highest in the outer zone. Induced expression of TREM2 occurred coincident with detection of thioflavine-S-positive amyloid deposits. Transfection studies revealed that expression of TREM2 correlated negatively with motility, but correlated positively with the ability of microglia to stimulate CD4 + T-cell proliferation, TNF (tumour necrosis factor) and CCL2 (chemokine ligand 2) production, but not IFNγ (interferon γ) production. TREM2 expression also showed a positive correlation with amyloid phagocytosis in unactivated cells. However, activating cells with LPS (lipopolysaccharide), but not IFNγ, reduced the correlation between TREM2 expression and phagocytosis. Transfection of Tmem176b into both microglial and macrophage cell lines increased apoptosis. Taken together, these data suggest that, in vivo , Tmem176b + cells in closest apposition to amyloid may be the least able to clear amyloid. Conversely, the phagocytic TREM2 + microglia on the plaque outer zones are positioned to capture and present self-antigens to CNS (central nervous system)-infiltrating lymphocytes without promoting pro-inflammatory lymphocyte responses. Instead, plaque-associated TREM2 + microglia have the potential to evoke neuroprotective immune responses that may serve to support CNS function during pro-inflammatory anti-amyloid immune therapies.
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title_short	Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease
url	https://doi.org/10.1042/AN20100010 https://doaj.org/article/82d86abdff8f47fb87f24b4052f5cd1e https://doaj.org/toc/1759-0914 https://doaj.org/toc/1759-9091
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author2	Angie E Garcia Bor-Kai Hsiung Katherine M Lo Jonathan M Doose J Cameron Thrash Anna K Stalder Matthias Staufenbiel Harald Neumann Monica J Carson
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up_date	2024-07-04T00:41:06.637Z
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Dual Induction of TREM2 and Tolerance-Related Transcript, Tmem176b, in Amyloid Transgenic Mice: Implications for Vaccine-Based Therapies for Alzheimer's Disease

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