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TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease

ABSTRACT: TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease

PROVIDER: PRJNA548198 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9264270.fastq.gz	Fastqsanger.gz
	SRR9264280.fastq.gz	Fastqsanger.gz
	SRR9264290.fastq.gz	Fastqsanger.gz
	SRR9264300.fastq.gz	Fastqsanger.gz
	SRR9264310.fastq.gz	Fastqsanger.gz

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Project description:TREM2 plays multiple functional roles in microglia and variants are associated with increased risks of Alzheimer’s disease (AD). CD33 polymorphisms are protective. Here we have contrasted cellular pathology in human post mortem brain with and without AD to test mechanisms associated with the differential genetic risks conferred by R47H and R62H TREM2 variants (TREM2var) with and without heterozygosity for the protective rs3865344 CD33 polymorphism. Epistasis between CD33 and TREM2 was demonstrated by both relative normalisation of differences in β-amyloid load and microglial transcriptomic responses to β-amyloid with the TREM2var. Controlling for CD33 genotype, microglial transcriptional responses to increasing β-amyloid were lower for TREM2var, particularly for R47H. R62H microglial signatures were distinguished from those of R47H by upregulation of genes associated with the MHC Class Ib response and phagocytosis. By contrast, TREM2var astrocytes differentially expressed greater numbers of genes than for the common allele (CV), including those involved in β-amyloid clearance pathways. Differential gene expression with increasing β-amyloid suggested upregulation of the β-amyloid production pathway in R62H excitatory neurons and lower enrichment for pathways positively adaptive to pathology in CV inhibitory neurons for both TREM2var. Exploratory bulk tissue proteomics support these observations with evidence for adaptive plasticity in response to β-amyloid pathology in CV tissue not found for the TREM2var which showed evidence for integrated stress responses and increased β-amyloid synthesis. Together, these results highlight differences in molecular pathology between the TREM2var risk variants. They describe impacts on mechanisms of AD risk mediated by secondary effects on astroglial and neuronal function, as well as the primary microglial functional pathology. Demonstration of strong epistasis between TREM2 and CD33 with AD supports the therapeutic potential of modulators of CD33 expression or its inhibition.

Project description:Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions within the brain, playing roles in neurotoxicity/neuroprotection, release of inflammatory and anti-inflammatory cytokines, and in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that modulates intracellular signaling networks, and these proteins are essential regulators of the transition from homeostatic to activated microglia. Recent findings support a TREM2-independent molecular signature that is involved in the early transition of homeostatic to disease-associated microglia (DAM), with the next sequential step of DAM activation from stage 1 to stage 2 being TREM2-dependent. However, the underlying mechanisms determining how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown. We isolated primary microglia from C57BL/6 wild-type (WT) controls, Trem2 knock-out (KO), and Tyrobp KO mice at post-natal day 0-3. Cells were treated with Alzheimer’s disease (AD)-relevant stimuli, such as amyloid beta (Aβ) oligomers or fibrils, or ‘neuroinflammatory-like’ stimuli, such as lipopolysaccharide (LPS). We explored protein and gene expression in the presence or absence of inhibitors of the TREM2/TYROBP downstream signaling pathway. We also performed a high-throughput Olink proteomic analysis of conditioned media from WT, Trem2 KO, and Tyrobp KO stimulated with either LPS or Aβ oligomers or fibrils. Our results show that the absence of either TREM2 or TYROBP is associated with increased basal levels of phosphorylated ERK in primary microglia compared to WT controls. In addition, Trem2 KO and Tyrobp KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Aβ oligomers or LPS leads to differential protein and gene expression in cells lacking TREM2 or TYROBP. The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggest their essential roles not only in microglial homeostasis but also in their activation in response to different stimuli.

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TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease

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