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

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

doi:10.1016/j.neurobiolaging.2018.04.019

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

263 Downloads (Pure)

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.

Original language	English
Pages (from-to)	151-166
Number of pages	16
Journal	Neurobiology of Aging
Volume	69
Early online date	17 May 2018
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.04.019
Publication status	Published - 1 Sept 2018

Keywords

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

Access to Document

10.1016/j.neurobiolaging.2018.04.019

Loss of Trem2 in_CARBAJOSA_Firstonline17May2018_GOLD VoR (CC BY)Final published version, 2.92 MBLicence: CC BY

Cite this

Carbajosa, G., Malki, K., Lawless, N., Wang, H., Ryder, J. W., Wozniak, E., Wood, K., Mein, C. A., Dobson, R. J. B., Collier, D. A., O'Neill, M. J., Hodges, A. K., & Newhouse, S. J. (2018). Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain. Neurobiology of Aging, 69, 151-166. https://doi.org/10.1016/j.neurobiolaging.2018.04.019

@article{4222f3fdc6434f1d932299f305cbb886,

title = "Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain",

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",

author = "Guillermo Carbajosa and Karim Malki and Nathan Lawless and Hong Wang and Ryder, {John W.} and Eva Wozniak and Kristie Wood and Mein, {Charles A.} and Dobson, {Richard J.B.} and Collier, {David A.} and O'Neill, {Michael J.} and Hodges, {Angela K.} and Newhouse, {Stephen J.}",

year = "2018",

month = sep,

day = "1",

doi = "10.1016/j.neurobiolaging.2018.04.019",

language = "English",

volume = "69",

pages = "151--166",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain

AU - Carbajosa, Guillermo

AU - Malki, Karim

AU - Lawless, Nathan

AU - Wang, Hong

AU - Ryder, John W.

AU - Wozniak, Eva

AU - Wood, Kristie

AU - Mein, Charles A.

AU - Dobson, Richard J.B.

AU - Collier, David A.

AU - O'Neill, Michael J.

AU - Hodges, Angela K.

AU - Newhouse, Stephen J.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

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 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.

KW - Alzheimer's disease

KW - Endothelial cells

KW - Knockout mouse model

KW - RNA-Seq

KW - TREM2

KW - Weighted gene coexpression network analysis

UR - http://www.scopus.com/inward/record.url?scp=85048526158&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.04.019

DO - 10.1016/j.neurobiolaging.2018.04.019

M3 - Article

AN - SCOPUS:85048526158

SN - 0197-4580

VL - 69

SP - 151

EP - 166

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this