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

Publication date: September 2018
Source:Neurobiology of Aging, Volume 69
Author(s): Guillermo Carbajosa, Karim Malki, Nathan Lawless, Hong Wang, John W. Ryder, Eva Wozniak, Kristie Wood, Charles A. Mein, Richard J.B. Dobson, David A. Collier, Michael J. O'Neill, Angela K. Hodges, Stephen J. Newhouse
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.



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