Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease

Jiang, Teng; Tan, Lan; Zhu, Xi-Chen; Zhang, Qiao-Quan; Cao, Lei; Tan, Meng-Shan; Gu, Ling; Wang, Hui-Fu; Ding, ZhengZheng; Yu, Jin‐Tai

doi:10.1038/npp.2014.164

Cited by 229 publications

(219 citation statements)

References 38 publications

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“…Genetic depletion studies of TREM2 or DAP12 in primary mouse microglia or the microglial BV2 cell line have demonstrated that pro-inflammatory cytokine levels (including IL-1␤, TNF␣, and IL-6) are significantly increased following co-incubation with bacterial lipopolysaccharide (27), apoptotic neurons (24), or A␤ (50). Overexpression of microglial TREM2, however, suppressed this excessive cytokine production under the same stimulatory conditions (27).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of microglial TREM2, however, suppressed this excessive cytokine production under the same stimulatory conditions (27). Furthermore, TREM2 deficiency has been shown to result in reduced phagocytic activity of apoptotic neurons (24,28,29), A␤ (50,51), and E. coli (51) by microglia. A recent report elegantly demonstrated a direct role for TREM2 in facilitating phagocytosis both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Atagi

Liu

Painter

et al. 2015

Journal of Biological Chemistry

408

410

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Background: TREM2 is associated with several neurodegenerative diseases. Results: ApoE bound to TREM2 and increased phagocytosis of apoptotic neurons by microglia. Alzheimer disease (AD) risk-associated TREM2-R47H mutant had a reduced binding to apoE. Conclusion: ApoE is a novel ligand for TREM2. Interaction between apoE and TREM2 likely regulates phagocytosis of apoEbound apoptotic neurons. Significance: Interaction between two AD risk-associated proteins modulates microglial function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Atagi

Liu

Painter

et al. 2015

Journal of Biological Chemistry

408

410

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“…Therefore, it remains unknown if, and to what extent, complete depletion of TREM2 affects Aβ catabolism. Interestingly, overexpression of TREM2 in a mouse model of AD afforded protection against AD progression through the modulation of microglia functions (Jiang, et al, 2014a). …”

Section: Introductionmentioning

confidence: 99%

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

Zhu

Herrmann

et al. 2015

Neurobiology of Aging

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Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2(-/-) mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. | P a g e AbstractDysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly upregulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2 -/-mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation, but does not noticeably modulate the pathogenesis of experimental prion infections.

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“…-/-mice did not develop spontaneous demyelination, we wanted to determine (35)(36)(37). Moreover, we found that Trem2 was not expressed in astrocytes or ODC precursors after 4 weeks of cuprizone feeding, while its expression in microglia was elevated (Supplemental Figure 2).…”

Section: Trem2 Is Required For Myelin Debris Removal and Remyelinatiomentioning

confidence: 99%

TREM2 sustains microglial expansion during aging and response to demyelination

Poliani¹,

Wang²,

Fontana³

et al. 2015

J. Clin. Invest.

377

401

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Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter

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Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease

Cited by 229 publications

References 38 publications

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

TREM2 sustains microglial expansion during aging and response to demyelination

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