TREM2, microglia, and Alzheimer’s disease

Qin, Qi; Teng, Zhao‐Qian; Liu, Chang‐Mei; Li, Qian; Yin, Yun; Tang, Yi

doi:10.1016/j.mad.2021.111438

Cited by 108 publications

(69 citation statements)

References 136 publications

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“…Increasing evidence suggests that the rare variants of TREM2 can promote the development of amyloid and tau pathologies due to the dysfunction of microglia ( Gratuze et al, 2018 ). Also, TREM2 can participate in the interaction with other biomarkers including APOE ( Qin et al, 2021 ). Collectively, Trem2 acts as the immune checkpoint and the scavenger receptor to clear harmful stimuli in the regulation of neurocyte survival ( Hickman et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Liu

Pan

2021

Front. Genet.

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BackgroundAs the most common neurodegenerative disease, Alzheimer’s disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration.MethodsThe gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further.ResultsThere was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR.ConclusionA model based on immune cell infiltration might be used to forecast AD patients’ diagnosis, and it provided a new perspective for AD treatment targets.

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Section: Introductionmentioning

confidence: 99%

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Liu

Pan

2021

Front. Genet.

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“…TREM2 is a type of immunoglobulin receptor highly expressed on microglial cells and plays a critical role in the negative regulation of autoimmune and inflammatory processes [ 17 ]. TREM2 interacts with its adaptor protein, DAP12, to transduce signals.…”

Section: Introductionmentioning

confidence: 99%

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

Long

Gao

et al. 2021

Brain Sciences

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Background: TREM2 expressed on microglia plays an important role in modulating inflammation in neurodegenerative diseases. It remains unknown whether TREM2 modulates hyperglycemia-induced microglial inflammation. Methods: We investigated the molecular function of TREM2 in high glucose-induced microglial inflammation using western blotting, qPCR, ELISA, pulldown, and co-IP methods. Results: Our data showed that in high glucose-induced BV2 cells, TREM2 was increased, and the proinflammatory cytokine IL-1β was increased. TREM2 knockout (KO) attenuated the proinflammatory cytokine IL-1β; conversely, TREM2 overexpression (OE) exacerbated IL-1β expression. Furthermore, we found that high glucose promoted the interaction of TREM2 with NLRP3. TREM2 KO abolished the interaction of TREM2 with NLRP3, while TREM2 OE enhanced the interaction. Moreover, TREM2 KO reduced high glucose-induced NLRP3 inflammasome activation, and TREM2 OE augmented high glucose-induced NLRP3 inflammasome activation, indicating that high glucose enhances the expression of TREM2, which activates the NLRP3 inflammasome. To further clarify whether the NLRP3 signaling pathway mediates the TREM2-regulated inflammatory response, we blocked the NLRP3 inflammasome by knocking out NLRP3 and treating cells with a caspase1 inhibitor, which decreased the levels of the IL-1β proinflammatory cytokine but did not affect the high glucose-induced expression of TREM2. Conclusions: TREM2 modulates high glucose-induced microglial inflammation via the NLRP3 signaling pathway.

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“…Neuroinflammation surrounding Aβ plaques manifests as one of the pathological features in AD patients ( 13 , 41 , 42 ), and genome-wide association studies (GWAS) have suggested etiological involvement of neuroinflammation in AD development ( 43 , 44 , 45 ). We thus analyzed the neuroinflammatory status of three mouse lines ( App NL-F , App NL-F Psen1 P117L , and App NL-G-F ) by immunofluorescence using antibodies against Aβ (82E1), microglia (Iba1), and astrocytes (anti-GFAP).…”

Section: Resultsmentioning

confidence: 99%

A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide

Sato

Watamura

Fujioka

et al. 2021

Journal of Biological Chemistry

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Please cite this article as: RRH: Improved model of Alzheimer's disease This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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TREM2, microglia, and Alzheimer’s disease

Cited by 108 publications

References 136 publications

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

TREM2 Regulates High Glucose-Induced Microglial Inflammation via the NLRP3 Signaling Pathway

A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide

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