PHAGO Publications

17/05/2018

Loss of Trem2 in microglia leads to widespread disruption of cell co-expression networks in mouse brain

Neurobiol. Aging - G. Carbajosa, K. Malki, N. Lawless, H. Wang, J.W. Ryder, E. Wozniak, K. Wood, C.A. Mein, R.J.B. Dobson, D.A. Collier, M.J. O’Neill, A.K. Hodges, S.J. Newhouse

G. Carbajosa, K. Malki, N. Lawless, H. Wang, J.W. Ryder, E. Wozniak, K. Wood, C.A. Mein, R.J.B. Dobson, D.A. Collier, M.J. O’Neill, A.K. Hodges, S.J. Newhouse

DOI 10.1016/j.neurobiolaging.2018.04.019

 

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 towards a more central role for the Amyloid Precursor Protein (App) 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 signalling hub, suggesting an underlying link between immune response and vascular disease in dementia.

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies.