RT Journal Article
SR Electronic
T1 Loss of Trem2 in microglia leads to widespread disruption of cell co-expression networks in mouse brain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 248757
DO 10.1101/248757
A1 Guillermo Carbajosa
A1 Karim Malki
A1 Nathan Lawless
A1 Hong Wang
A1 John W. Ryder
A1 Eva Wozniak
A1 Kristie Wood
A1 Charles A. Mein
A1 Richard J.B. Dobson
A1 David A. Collier
A1 Michael J. O’Neill
A1 Angela K. Hodges
A1 Stephen J. Newhouse
YR 2018
UL http://biorxiv.org/content/early/2018/01/17/248757.abstract
AB 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.