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Neurobiol Aging. 2018 Sep;69:151-166. doi: 10.1016/j.neurobiolaging.2018.04.019. Epub 2018 May 17.

Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain.

Author information

1
Department of Biostatistics and Health Informatics, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK. Electronic address: guillermo.carbajosa_antona@kcl.ac.uk.
2
Eli Lilly and Company, Windlesham, UK.
3
Eli Lilly and Company, Indianapolis, IN, USA.
4
Barts and the London Genome Centre, John Vane Science Centre, Barts and the London School of Medicine and Dentistry, London, UK.
5
Department of Biostatistics and Health Informatics, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK; NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK; Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK.
6
Maurice Wohl Clinical Neuroscience Institute James Black Centre Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.

Abstract

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.

KEYWORDS:

Alzheimer's disease; Endothelial cells; Knockout mouse model; RNA-Seq; TREM2; Weighted gene coexpression network analysis

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