Dataset Information

Subtle changes in brain expression modules in Alzheimer’s disease TREM2 carriers compared to non-carriers

ABSTRACT: Background: Rare heterozygous coding variants with a large effect on the risk of developing late-onset Alzheimer's disease (similar to ApoE4, OR 2.90-5.05) have been identified in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene. However, little is known about the mechanisms through which Trem2 maladjustment may lead to AD Methods: We performed differential expression and co-expression network analysis on samples obtained from 5 (mainly 2) brain areas from individuals carrying the TREM2 variant known to increase the risk of Alzheimer’s and others using RNA-Seq to obtain a systems level view of the effects of the TREM2 mutation Results: The absence of Trem2 has a stronger effect at an earlier age with the number of differential expressed (DE) genes being 17-fold greater at 4 months than at 8 months in cortex. By integrating DE genes and network analysis we discovered gene clusters associated with the disruption of blood vessel formation at 4 months of age and protein targeting primarily affecting the hippocampus at 8 months. Further integration of cell type and ontology information revealed a large disruption of a gene module enriched for endothelial cell markers coinciding with the module enriched for neuron cell markers having weaker connections to modules with oligodendrocyte and astrocyte identities. The module with neuronal identity has decreased expression only in the KO where it has closer association with a new module enriched for phagocytic functions Conclusions: Combining gene co-expression and differential expression analysis on brains of carriers of TREM2 mutations we demonstrate that the presence of damaging TREM2 mutation produce subtle disruptions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140841 | GEO | 2025/10/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell-type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial gene-enriched subnetwork at 4 months, including a shift toward a more central role for the amyloid precursor protein gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub, suggesting an underlying link between immune response and vascular disease in dementia. Methods: We performed differential expression and co-expression network analysis on a RNA-Seq profiled Trem2 knockout (KO) mouse using two brain areas sampled at 4- and 8-months to obtain a systems level view of the effects of the absence of Trem2. Results: The absence of Trem2 has a stronger effect at an earlier age with the number of differential expressed (DE) genes being 17-fold greater at 4 months than at 8 months in cortex. By integrating DE genes and network analysis, we discovered gene clusters associated with the disruption of blood vessel formation at 4 months of age and protein targeting primarily affecting the hippocampus at 8 months. Further integration of cell type and ontology information revealed a large disruption of a gene module enriched for endothelial cell markers coinciding with the module enriched for neuron cell markers having weaker connections to modules with oligodendrocyte and astrocyte identities. The module with neuronal identity has decreased expression only in the KO where it has closer association with a new module enriched for phagocytic functions. Conclusions: Combining gene co-expression and differential expression analysis on a newly generated RNA-Seq profiled Trem2 KO mouse demonstrate that the absence of Trem2 produces a disruption which mainly affects endothelialon related processes at 4 months of age. It results in a ripple effect that disrupts the cross-talk of other cell types at 8 months, including reduced expression of a gene module enriched in neuron related functions and a shift towards a more central role for App. This study reveals an unexpected role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signaling hub suggesting new paths for investigation at the intersection between Trem2, Alzheimer’s disease and vascular dementia.

Project description:TREM2 is a microglial cell surface receptor, with risk mutations linked to Alzheimer’s disease (AD), including R47H. TREM2 signalling via SYK aids phagocytosis, chemotaxis, survival, and changes to microglial activation state. In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid, and prevents microglial activation. The R47H mutation is proposed to reduce TREM2 ligand binding. We investigated cell phenotypes of the R47H mutant and TREM2 KO in a model of human microglia, and compared their transcriptional signatures, to determine the mechanism by which R47H TREM2 disrupts function. We generated human microglia-like iPSC-macrophages (pMac) from isogenic induced pluripotent stem cell (iPSC) lines, with homozygous R47H mutation or TREM2 knockout (KO). We firstly validated the effect of the R47H mutant on TREM2 surface and subcellular localization in pMac. To assess microglial phenotypic function we measured phagocytosis of dead neurons, cell morphology, directed migration, survival, and LPS-induced inflammation. We performed bulk RNA-seq, comparing significant differentially-expressed genes (DEGs: p<0.05) between the R47H and KO versus WT, and bioinformatically predicted potential upstream regulators of TREM2-mediated gene expression. Altered gene expression in the R47H TREM2 pMac overlapped by 90% with the TREM2 KO, and was characterized by dysregulation of genes involved with immunity, proliferation, activation, chemotaxis and adhesion. Downregulated mediators of ECM adhesion included the vitronectin receptor αVβ3, and consequently R47H TREM2 pMac adhered weakly to vitronectin compared with WT pMac. To counteract these transcriptional defects, we investigated TGFβ1, as a candidate upstream regulator. TGFβ1 failed to rescue vitronectin adhesion of pMac, although improved αVβ3 expression. The R47H mutation is not sufficient to cause gross phenotypic defects of human pMac under standard culture conditions. However, overlapping transcriptional defects with TREM2 KO supports the hypothesised partial loss-of-function effects of the R47H mutation. Furthermore, transcriptomics can guide us to more subtle phenotypic defects in the R47H cells, such as reduced cell adhesion, and can be used to predict targets for therapeutic intervention.

Dataset Information

Subtle changes in brain expression modules in Alzheimer’s disease TREM2 carriers compared to non-carriers

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets