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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [scRNA-seq]

ABSTRACT: scRNA-sequencing of human xenotransplanted microglia isogenic for TREM2 after exposure to amyloid pathology

ORGANISM(S): Homo sapiens

PROVIDER: GSE158234 | GEO | 2020/09/19

REPOSITORIES: GEO

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer’s pathology in vivo [RNA-seq]

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo [bulk RNA-seq]

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Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's Disease model

Project description:TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer’s Disease (AD) risk. In mouse models of amyloid b (Ab) accumulation, defective TREM2 function affects microglial response to Ab plaques exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior and tempered glial inflammatory response. We further showed that a variant of AL002c has been given safely in a first-in-human phase I clinical trial and engages TREM2 based on CSF biomarkers. We conclude that AL002c is a promising candidate for AD therapy.

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

Project description:CD33-/- and/or TREM2-/- mice were crossed with the 5xFAD mouse model of Alzheimer’s disease to generate single and double CD33/TREM2 knock-out mice on 5xFAD background. Transcriptome and gene expression analyses were performed to analyze the impact of CD33 and/or TREM2 knock-out on the transcriptome of microglia in the context of amyloid pathology. The results revealed that CD33 and/or TREM2 knock-out reprogrammed microglial gene expression signatures in 5xFAD mice in an age-dependent manner. Differential gene expression in 5xFAD;CD33-/- microglia depended on the presence of TREM2. These data suggest that TREM2 acts downstream of CD33.

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo

Project description:This SuperSeries is composed of the SubSeries listed below.

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Transcriptomic and functional deficits in human TREM2-/- microglia impair response to Alzheimer's pathology in vivo

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Blood-borne macrophages contribute to Alzheimer's disease modification through a TREM2-independent pathway

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