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.

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 (APP^KM670/671NL/PSEN1^Δexon9) 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 micr

SUBMITTER: Haure-Mirande JV 

PROVIDER: S-EPMC6494440 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature