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

Guillermo Carbajosa; Karim Malki; Nathan  Lawless; Hong  Wang; John W. Ryder; Eva  Wozniak; Charles A. Mein; Richard J.B. Dobson; David A. Collier; Michael J O'Neill; Angela K. Hodges; Stephen J. Newhouse

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

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

Eli Lilly & Co Ltd

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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.

Original language	English
Pages (from-to)	151-166
Journal	Neurobiology of Aging
Volume	69
Early online date	17 May 2018
Publication status	Published - Sept 2018

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Loss of Trem2 in microglia_CARBAJOSA_Firstonline17May2018_GOLD VoR (CC BY)Final published version, 2.92 MBLicence: CC BY

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@article{8b75b4a0f9eb4469ad54d19221095724,

title = "Loss of Trem2 in microglia leads to widespread disruption of cell co-expression 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 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.",

author = "Guillermo Carbajosa and Karim Malki and Nathan Lawless and Hong Wang and Ryder, {John W.} and Eva Wozniak 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,

language = "English",

volume = "69",

pages = "151--166",

journal = "Neurobiology of Aging",

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

AU - Carbajosa , Guillermo

AU - Malki, Karim

AU - Lawless, Nathan

AU - Wang, Hong

AU - Ryder, John W.

AU - Wozniak, Eva

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

Y1 - 2018/9

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 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.

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.

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M3 - Article

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 co-expression networks in mouse brain

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