Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden

Jean Vianney Haure-Mirande, Minghui Wang, Mickael Audrain, Tomas Fanutza, Soong Ho Kim, Szilvia Heja, Benjamin Readhead, Joel T. Dudley, Robert D. Blitzer, Eric E. Schadt, Bin Zhang, Sam Gandy, Michelle E. Ehrlich

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Integrative gene network approaches enable new avenues of exploration that implicate causal genes in sporadic late-onset Alzheimer’s disease (LOAD) pathogenesis, thereby offering novel insights for drug-discovery programs. We previously constructed a probabilistic causal network model of sporadic LOAD and identified TYROBP/DAP12, encoding a microglial transmembrane signaling polypeptide and direct adapter of TREM2, as the most robust key driver gene in the network. Here, we show that absence of TYROBP/DAP12 in a mouse model of AD-type cerebral Aβ amyloidosis (APPKM670/671NL/PSEN1Δexon9) recapitulates the expected network characteristics by normalizing the transcriptome of APP/PSEN1 mice and repressing the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia (DAM), including Trem2, complement (C1qa, C1qb, C1qc, and Itgax), Clec7a and Cst7. Importantly, we show that constitutive absence of TYROBP/DAP12 in the amyloidosis mouse model prevented appearance of the electrophysiological and learning behavior alterations associated with the phenotype of APPKM670/671NL/PSEN1Δexon9 mice. Our results suggest that TYROBP/DAP12 could represent a novel therapeutic target to slow, arrest, or prevent the development of sporadic LOAD. These data establish that the network pathology observed in postmortem human LOAD brain can be faithfully recapitulated in the brain of a genetically manipulated mouse. These data also validate our multiscale gene networks by demonstrating how the networks intersect with the standard neuropathological features of LOAD.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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Molecular Pathology
Alzheimer Disease
Gene Regulatory Networks
Phenotype
Microglia
Brain
Amyloidosis
Drug Discovery
Transcriptome
Genes
Amyloid angiopathy
Learning
Pathology
Peptides

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden. / Haure-Mirande, Jean Vianney; Wang, Minghui; Audrain, Mickael; Fanutza, Tomas; Kim, Soong Ho; Heja, Szilvia; Readhead, Benjamin; Dudley, Joel T.; Blitzer, Robert D.; Schadt, Eric E.; Zhang, Bin; Gandy, Sam; Ehrlich, Michelle E.

In: Molecular Psychiatry, 01.01.2018.

Research output: Contribution to journalArticle

Haure-Mirande, Jean Vianney ; Wang, Minghui ; Audrain, Mickael ; Fanutza, Tomas ; Kim, Soong Ho ; Heja, Szilvia ; Readhead, Benjamin ; Dudley, Joel T. ; Blitzer, Robert D. ; Schadt, Eric E. ; Zhang, Bin ; Gandy, Sam ; Ehrlich, Michelle E. / Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden. In: Molecular Psychiatry. 2018.
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abstract = "Integrative gene network approaches enable new avenues of exploration that implicate causal genes in sporadic late-onset Alzheimer’s disease (LOAD) pathogenesis, thereby offering novel insights for drug-discovery programs. We previously constructed a probabilistic causal network model of sporadic LOAD and identified TYROBP/DAP12, encoding a microglial transmembrane signaling polypeptide and direct adapter of TREM2, as the most robust key driver gene in the network. Here, we show that absence of TYROBP/DAP12 in a mouse model of AD-type cerebral Aβ amyloidosis (APPKM670/671NL/PSEN1Δexon9) recapitulates the expected network characteristics by normalizing the transcriptome of APP/PSEN1 mice and repressing the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia (DAM), including Trem2, complement (C1qa, C1qb, C1qc, and Itgax), Clec7a and Cst7. Importantly, we show that constitutive absence of TYROBP/DAP12 in the amyloidosis mouse model prevented appearance of the electrophysiological and learning behavior alterations associated with the phenotype of APPKM670/671NL/PSEN1Δexon9 mice. Our results suggest that TYROBP/DAP12 could represent a novel therapeutic target to slow, arrest, or prevent the development of sporadic LOAD. These data establish that the network pathology observed in postmortem human LOAD brain can be faithfully recapitulated in the brain of a genetically manipulated mouse. These data also validate our multiscale gene networks by demonstrating how the networks intersect with the standard neuropathological features of LOAD.",
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AU - Wang, Minghui

AU - Audrain, Mickael

AU - Fanutza, Tomas

AU - Kim, Soong Ho

AU - Heja, Szilvia

AU - Readhead, Benjamin

AU - Dudley, Joel T.

AU - Blitzer, Robert D.

AU - Schadt, Eric E.

AU - Zhang, Bin

AU - Gandy, Sam

AU - Ehrlich, Michelle E.

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