Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice

Abstract Background Alzheimer’s Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOEε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Recent studies showed that APOE binds t...

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Main Authors: Nicholas F. Fitz, Cody M. Wolfe, Brittany E. Playso, Richard J. Biedrzycki, Yi Lu, Kyong Nyon Nam, Iliya Lefterov, Radosveta Koldamova
Format: Article
Language:English
Published: BMC 2020-07-01
Series:Molecular Neurodegeneration
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13024-020-00394-4
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author Nicholas F. Fitz
Cody M. Wolfe
Brittany E. Playso
Richard J. Biedrzycki
Yi Lu
Kyong Nyon Nam
Iliya Lefterov
Radosveta Koldamova
author_facet Nicholas F. Fitz
Cody M. Wolfe
Brittany E. Playso
Richard J. Biedrzycki
Yi Lu
Kyong Nyon Nam
Iliya Lefterov
Radosveta Koldamova
author_sort Nicholas F. Fitz
collection DOAJ
description Abstract Background Alzheimer’s Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOEε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Recent studies showed that APOE binds to TREM2, thus raising the possibility of an APOE-TREM2 interaction that can modulate AD pathology. Methods The aim of this study was to investigate this interaction using complex AD model mice - a crossbreed of Trem2ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms (APP/E3 and APP/E4 respectively), and their WT littermates (E3 and E4), and evaluate cognition, steady-state amyloid load, plaque compaction, plaque growth rate, glial response, and brain transcriptome. Results In both, APP/E3 and APP/E4 mice, Trem2 deletion reduced plaque compaction but did not significantly affect steady-state plaque load. Importantly, the lack of TREM2 increased plaque growth that negatively correlated to the diminished microglia barrier, an effect most pronounced at earlier stages of amyloid deposition. We also found that Trem2 deficiency significantly decreased plaque-associated APOE protein in APP/E4 but not in APP/E3 mice in agreement with RNA-seq data. Interestingly, we observed a significant decrease of Apoe mRNA expression in plaque-associated microglia of APP/E4/Trem2ko vs APP/E4 mice. The absence of TREM2, worsened cognitive performance in APP transgenic mice but not their WT littermates. Gene expression analysis identified Trem2 signature - a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all genotypes including APP and WT littermates. Furthermore, we identified sets of genes that were affected in TREM2- and APOE isoform-dependent manner. Among them were Clec7a and Csf1r upregulated in APP/E4 vs APP/E3 mice, a result further validated by in situ hybridization analysis. In contrast, Tyrobp and several genes involved in the C1Q complement cascade had a higher expression level in APP/E3 versus their APP/E4 counterparts. Conclusions Our data demonstrate that lack of Trem2 differentially impacts the phenotype and brain transcriptome of APP mice expressing human APOE isoforms. The changes probably reflect the different effect of APOE isoforms on amyloid deposition.
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spelling doaj.art-a40b5f4e0bbc4c3f9b946ef0cb70ce102022-12-21T23:42:34ZengBMCMolecular Neurodegeneration1750-13262020-07-0115112110.1186/s13024-020-00394-4Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 miceNicholas F. Fitz0Cody M. Wolfe1Brittany E. Playso2Richard J. Biedrzycki3Yi Lu4Kyong Nyon Nam5Iliya Lefterov6Radosveta Koldamova7Department of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghDepartment of Environmental & Occupational Health, University of PittsburghAbstract Background Alzheimer’s Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOEε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Recent studies showed that APOE binds to TREM2, thus raising the possibility of an APOE-TREM2 interaction that can modulate AD pathology. Methods The aim of this study was to investigate this interaction using complex AD model mice - a crossbreed of Trem2ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms (APP/E3 and APP/E4 respectively), and their WT littermates (E3 and E4), and evaluate cognition, steady-state amyloid load, plaque compaction, plaque growth rate, glial response, and brain transcriptome. Results In both, APP/E3 and APP/E4 mice, Trem2 deletion reduced plaque compaction but did not significantly affect steady-state plaque load. Importantly, the lack of TREM2 increased plaque growth that negatively correlated to the diminished microglia barrier, an effect most pronounced at earlier stages of amyloid deposition. We also found that Trem2 deficiency significantly decreased plaque-associated APOE protein in APP/E4 but not in APP/E3 mice in agreement with RNA-seq data. Interestingly, we observed a significant decrease of Apoe mRNA expression in plaque-associated microglia of APP/E4/Trem2ko vs APP/E4 mice. The absence of TREM2, worsened cognitive performance in APP transgenic mice but not their WT littermates. Gene expression analysis identified Trem2 signature - a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all genotypes including APP and WT littermates. Furthermore, we identified sets of genes that were affected in TREM2- and APOE isoform-dependent manner. Among them were Clec7a and Csf1r upregulated in APP/E4 vs APP/E3 mice, a result further validated by in situ hybridization analysis. In contrast, Tyrobp and several genes involved in the C1Q complement cascade had a higher expression level in APP/E3 versus their APP/E4 counterparts. Conclusions Our data demonstrate that lack of Trem2 differentially impacts the phenotype and brain transcriptome of APP mice expressing human APOE isoforms. The changes probably reflect the different effect of APOE isoforms on amyloid deposition.http://link.springer.com/article/10.1186/s13024-020-00394-4Trem2APOETranscriptomicsMicrogliaNeuroinflammationAlzheimer’s disease
spellingShingle Nicholas F. Fitz
Cody M. Wolfe
Brittany E. Playso
Richard J. Biedrzycki
Yi Lu
Kyong Nyon Nam
Iliya Lefterov
Radosveta Koldamova
Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
Molecular Neurodegeneration
Trem2
APOE
Transcriptomics
Microglia
Neuroinflammation
Alzheimer’s disease
title Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
title_full Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
title_fullStr Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
title_full_unstemmed Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
title_short Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
title_sort trem2 deficiency differentially affects phenotype and transcriptome of human apoe3 and apoe4 mice
topic Trem2
APOE
Transcriptomics
Microglia
Neuroinflammation
Alzheimer’s disease
url http://link.springer.com/article/10.1186/s13024-020-00394-4
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