TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

Magno, Lorenza; Bunney, Tom D.; Mead, Emma; Svensson, Fredrik; Bictash, Magda

doi:10.1186/s13024-021-00436-5

Cited by 32 publications

(20 citation statements)

References 141 publications

(255 reference statements)

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“…Accumulating evidence suggests that the modulation of the TREM2/PLCG2 signaling pathway is a potential therapeutic candidate for AD [ 16 ]; however, the role of PLCG2 and the signaling networks associated with PLCG2 in the brain remain unclear. We identified differentially expressed genes and pathways by performing differential gene expression analysis on bulk RNA-Seq data from CN with 25th-percentile PLCG2 gene expression levels (low) and 75th-percentile PLCG2 gene expression levels (high).…”

Section: Discussionmentioning

confidence: 99%

“…PLCG2 is a membrane-associated enzyme that catalyzes the conversion of phospholipid PIP2 (1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate) to IP3 (1D-myo-inositol 1,4,5-trisphosphate) and DAG (diacylglycerol), which plays a crucial role in cell-surface receptor signal transduction [ 12 ]. In AD, the effect of PLCG2 might depend on the stage of neurodegeneration, the gene expression, the enzymatic activity, and the formation of intracellular signaling complexes in microglia [ 10 , 13 – 16 ]. Therefore, a better understanding of the role of PLCG2 in AD and microglia is needed for the development of PLCG2 -directed therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

et al. 2022

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Background Alzheimer’s disease (AD) is characterized by robust microgliosis and phenotypic changes that accompany disease pathogenesis. Accumulating evidence from genetic studies suggests the importance of phospholipase C γ 2 (PLCG2) in late-onset AD (LOAD) pathophysiology. However, the role of PLCG2 in AD is still poorly understood. Methods Using bulk RNA-Seq (N=1249) data from the Accelerating Medicines Partnership-Alzheimer’s Disease Consortium (AMP-AD), we investigated whether PLCG2 expression increased in the brains of LOAD patients. We also evaluated the relationship between PLCG2 expression levels, amyloid plaque density, and expression levels of microglia specific markers (AIF1 and TMEM119). Finally, we investigated the longitudinal changes of PLCG2 expression in the 5xFAD mouse model of AD. To further understand the role of PLCG2 in different signaling pathways, differential gene expression and co-expression network analyses were performed using bulk RNA-Seq and microglial single-cell RNA-Seq data. To substantiate the human analyses, we performed differential gene expression analysis on wild-type (WT) and inactivated Plcg2 mice and used immunostaining to determine if the differentially expressed genes/pathways were altered by microglial cell coverage or morphology. Results We observed significant upregulation of PLCG2 expression in three brain regions of LOAD patients and significant positive correlation of PLCG2 expression with amyloid plaque density. These findings in the human brain were validated in the 5xFAD amyloid mouse model, which showed disease progression-dependent increases in Plcg2 expression associated with amyloid pathology. Of note, increased Plcg2 expression levels in 5xFAD mice were abolished by reducing microglia. Furthermore, using bulk RNA-Seq data, we performed differential expression analysis by comparing cognitively normal older adults (CN) with 75th percentile (high) and 25th percentile (low) PLCG2 gene expression levels to identify pathways related to inflammation and the inflammatory response. The findings in the human brain were validated by differential expression analyses between WT and plcg2 inactivated mice. PLCG2 co-expression network analysis of microglial single-cell RNA-Seq data identified pathways related to the inflammatory response including regulation of I-kappaB/NF-kappa B signaling and response to lipopolysaccharide. Conclusions Our results provide further evidence that PLCG2 plays an important role in AD pathophysiology and may be a potential target for microglia-targeted AD therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

et al. 2022

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“…Expression of PLCG2 is increased in microglia surrounding amyloid plaques [ 139 ]. Further, PLCG2 is also known to colocalize with TREM2, and is assumed to be involved in TREM2 downstream signalling [ 139 , 140 ].…”

Section: Microglial Risk Factors and Their Functional Relevancementioning

confidence: 99%

Functional insight into LOAD-associated microglial response genes

Jonas

Jain

2022

Open Biol.

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Alzheimer's disease (AD) is characterized by the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), neuronal and synaptic loss and inflammation of the central nervous system (CNS). The majority of AD research has been dedicated to the understanding of two major AD hallmarks (i.e. Aβ and NFTs); however, recent genome-wide association studies (GWAS) data indicate neuroinflammation as having a critical role in late-onset AD (LOAD) development, thus unveiling a novel avenue for AD therapeutics. Recent evidence has provided much support to the innate immune system's involvement with AD progression; however, much remains to be uncovered regarding the role of glial cells, specifically microglia, in AD. Moreover, numerous variants in immune and/or microglia-related genes have been identified in whole-genome sequencing and GWAS analyses, including such genes as TREM2 , CD33 , APOE , API1 , MS4A , ABCA7 , BIN1 , CLU , CR1 , INPP5D , PICALM and PLCG2 . In this review, we aim to provide an insight into the function of the major LOAD-associated microglia response genes.

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“…We have also found that CSF1R deficiency significantly reduces the survival of microglia and increases the Trem2 mRNA level ( Cheng et al, 2021 ). TREM2, however, has also been shown to modulate the proliferation and survival of myeloid cells including microglia ( Gratuze et al, 2018 ; Magno et al, 2021 ). TREM2 deficiency in primary microglia results in cell cycle arrest at the G1/S checkpoint ( Zheng et al, 2017 ).…”

Section: Physiological Role Of Csf1r In the Central Nervous Systemmentioning

confidence: 99%

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

Duan

Wang

et al. 2021

Front. Aging Neurosci.

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The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

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TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

Cited by 32 publications

References 141 publications

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease

Functional insight into LOAD-associated microglial response genes

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders

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