DOI: 10.1101/499319Dec 19, 2018Paper

TREM2 R47H exacerbates immune response in Alzheimer's disease brain

BioRxiv : the Preprint Server for Biology
Olena KorvatskaWendy H Raskind

Abstract

The R47H variant in the microglial TREM2 receptor is a strong risk factor for Alzheimer's disease (AD). Loss-of-function mutations in TREM2 or its adaptor TYROBP cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, a systemic disease with early onset dementia. To characterize processes affected by the R47H we performed integrative network analysis of genes expressed in brains of AD patients with TREM2 R47H and sporadic AD without the TREM2 variant. In AD patients with TREM2 R47H we identified upregulation of interferon type I response and pro-inflammatory pathways, accompanied by induction of NKG2D stress ligands. In contrast, sporadic AD brains had few perturbed microglial and immune genes. In a human myeloid cell line, THP1, overexpression of normal TREM2 or its knockout revealed a profound effect of TREM2 dosage on gene networks. The effect of TREM2 R47H was complex, consistent with a partial loss of activity in conjunction with some dominant effect on pathways related to vasculature and angiogenesis. Changing the dosage of normal TREM2 in THP1 cells affected the IFN type 1 response signature, however, overexpression of TREM2 R47H was not sufficient to stimulate this pathway. We conclude that T...Continue Reading

Related Concepts

Alzheimer's Disease
Brain
Gene Expression
Genes
Interferons
Ligands
Subacute Sclerosing Panencephalitis
Up-Regulation (Physiology)
Cell Line, Tumor
Microglia

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