TREM2 expression in the brain and biological fluids in prion diseases

Díaz-Lucena, Daniela; Kruse, Niels; Thüne, Katrin; Schmitz, Matthias; Villar‐Piqué, Anna; Cunha, José Eriton Gomes da; Hermann, Péter; López-Pérez, Óscar; Andrés‐Benito, Pol; Ladogana, Anna; Calero, Miguel; Vidal, Enríc; Riggert, Joachim; Pineau, Hailey; Sim, Valerie L.; Zetterberg, Henrik; Blennow, Kaj; Rı́o, José Antonio del; Marín-Moreno, Alba; Espinosa, Juan Carlos; Torres, Juan María; Sánchez‐Valle, Raquel; Mollenhauer, Brit; Ferrer, Isidre; Zerr, Inga; Llorens, Franc

doi:10.1007/s00401-021-02296-1

Cited by 22 publications

(24 citation statements)

References 81 publications

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“…5A1). We also found top associations for the APOE , which codes for apolipoprotein E and is directly related to AD, cerebral amyloid angiopathy, PD and other neurological diseases 48 , and TREM2 , a receptor expressed in myeloid cells 2 and related to microglial biology, high risk of developing AD 49 and prion diseases 50 . In addition, the SORL1 gene, encoding the sortilin-related receptor and previously associated with early and late-onset Alzheimer’s disease 51 , was also found in the upper percentile with a high positive correlation with functional centrality.…”

Section: Discussionmentioning

confidence: 72%

Linking hubness, embryonic neurogenesis, transcriptomics and diseases in human brain networks

Diez

García-Moreno

Sainz

et al. 2022

Preprint

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Understanding the architectural principle that shapes the topology of the human connectome at its multiple spatial scales is a major challenge for systems neuroscience. This would provide key fundamental principles and a theory for browsing brain’s networks, to ultimately generate hypothesis and approach to which extent key structures might impact different brain pathologies. In this work, we propose the hypothesis that the centrality of the different brain nodes in the human connectome is a product of their embryogenic age, and accordingly, early-born nodes should display higher hubness, and viceversa for late-born nodes. We tested our hypothesis by identifying and segmenting eighteen macroregions with a well-known embryogenic age, over which we calculated nodes’ centrality in the structural and functional networks at different spatial resolutions. First, nodes’ structural centrality correlated with their embryogenic age, fully confirming our working hypothesis. However, at the functional level, distinct trends were found at different resolutions. Secondly, the difference in embryonic age between nodes inversely correlated with the probability of existence and the weights of the links. This indicated the presence of a temporal developmental gradient that shapes connectivity and where nodes connect more to nodes with a similar age. Finally, brain transcriptomic analysis revealed high association between embryonic age, structural-functional centrality and the expression of genes related to nervous system development and synapse regulation. Furthermore, the spatial expression of genes causally related to major neurological diseases was highly correlated with spatial maps of region centrality. Overall, these results support the hypothesis that the embryogenic age of brain regions shapes the topology of adult brain networks. Our results show two key principles, “preferential age attachment” and “older gets richer” on the wiring of the human brain, thus shedding new light on the relationship between brain development, transcriptomics, node centrality, and neurological diseases.

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Section: Discussionmentioning

confidence: 72%

Linking hubness, embryonic neurogenesis, transcriptomics and diseases in human brain networks

Diez

García-Moreno

Sainz

et al. 2022

Preprint

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“…To further verify how TREM2 plays the above role, we performed the following studies: we increased the level of TREM2 in BV2 cells by transfection with a TREM2 overexpression plasmid and promoted the overexpression of TREM2 in the mouse midbrain by lentiviral transfection. It should be noted that according to our experimental results, lentivirus infects cells in the mouse brain, including microglia and neurons, but under normal conditions, TREM2 is only expressed in microglia (Casali and Reed-Geaghan, 2021;Diaz-Lucena et al, 2021;Lv et al, 2021). This makes it impossible to prove that in vitro data is paralleled by the in vivo data.…”

Section: Discussionmentioning

confidence: 77%

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Huang

Yan

et al. 2021

Front. Neurosci.

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Parkinson’s disease is a neurodegenerative disorder with an inflammatory response as the core pathogenic mechanism. Previous human genetics findings support the view that the loss of TREM2 function will aggravate neurodegeneration, and TREM2 is one of the most highly expressed receptors in microglia. However, the role of TREM2 in the inflammatory mechanism of PD is not clear. In our study, it was found both in vivo and in vitro that the activation of microglia not only promoted the secretion of inflammatory factors but also decreased the level of TREM2 and inhibited the occurrence of autophagy. In contrast, an increase in the level of TREM2 decreased the expression of inflammatory factors and enhanced the level of autophagy through the p38 MAPK/mTOR pathway. Moreover, increased TREM2 expression significantly decreased the apoptosis of dopaminergic (DA) neurons and improved the motor ability of PD mice. In summary, TREM2 is an important link between the pathogenesis of PD and inflammation. Our study provides a new view for the mechanism of TREM2 in PD and reveals TREM2 as a potential therapeutic target for PD.

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“…Given the findings that the variants of TREM2 could markedly increase the risk of AD, this receptor has been a major focus in the neuroscience (62)(63)(64). Although studies have shown that TREM2 is exclusively expressed in microglia (62), double immunofluorescence staining has demonstrated that TREM2 is expressed in microglia (ionized calcium-binding adapter molecule 1), astrocytes (glial fibrillary acidic protein), and neurons (neuronal nucleus) in the brain (35,65).…”

Section: Discussionmentioning

confidence: 99%

Potential role of TREM2 in high cholesterol‑induced cell injury and metabolic dysfunction in SH‑SY5Y cells

et al. 2023

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Triggering receptor expressed on myeloid cells 2 (TREM2) is an important member of the immunoglobulin family of inflammatory stimulating receptors and is involved in a number of pathophysiological processes. The present study aimed to investigate the role of TREM2 in neurotoxicity induced by high cholesterol levels in SH-SY5Y cells and explore the potential mechanism. SH-SY5Y cells were routinely cultured and stimulated with a range of cholesterol concentrations. Cell viability was assessed using an MTT assay, morphological changes were observed, and the cell cycle distribution was measured using flow cytometry. Lipid deposition was measured by Oil red O staining, and the mRNA and protein expression levels of SRBEP-1 and SRBEP-2 were detected by quantitative PCR and western blotting, respectively. Moreover, the protein expression levels of BDNF, Copine-6, TREM1, TREM2, and key molecules of the Wnt signaling pathways were detected by western blotting. Finally, TREM2 was overexpressed to investigate its potential role in high cholesterol-induced neurotoxicity. The results showed that cell viability was significantly decreased in SH-SY5Y cells stimulated with cholesterol (0.1~100 µM) in a dose-and time-dependent manner. Stimulation with 100 µM cholesterol for 24 h resulted in morphological injuries, increased the proportion of SH-SY5Y cells at G0/G1, the degree of lipid accumulation, and the protein expression levels of sterol regulatory element binding protein (SREBP)1 and SREBP2, markedly decreased the protein expression levels of BDNF, Copine-6, and TREM2, and the p-β-catenin/β-catenin ratio, and increased the expression levels of nesfatin-1, TREM1 and the p-GSK3β/GSK3β ratio. Furthermore, the imbalanced expression of BDNF, Copine-6, nesfatin-1, and p-GSK3β induced by high cholesterol levels was reversed after overexpression of TREM2. These results suggest that a high concentration of cholesterol could induce cell injury and lipid deposition in SH-SY5Y cells and that the underlying mechanism may be associated with imbalanced TREM2 expression.

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TREM2 expression in the brain and biological fluids in prion diseases

Cited by 22 publications

References 81 publications

Linking hubness, embryonic neurogenesis, transcriptomics and diseases in human brain networks

Linking hubness, embryonic neurogenesis, transcriptomics and diseases in human brain networks

Triggering Receptor Expressed on Myeloid Cells 2 Protects Dopaminergic Neurons by Promoting Autophagy in the Inflammatory Pathogenesis of Parkinson’s Disease

Potential role of TREM2 in high cholesterol‑induced cell injury and metabolic dysfunction in SH‑SY5Y cells

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