Identification of Pre-symptomatic Gene Signatures That Predict Resilience to Cognitive Decline in the Genetically Diverse AD-BXD Model

Frontiers in Genetics
Sarah M NeunerCatherine C Kaczorowski

Abstract

Across the population, individuals exhibit a wide variation of susceptibility or resilience to developing Alzheimer's disease (AD). Identifying specific factors that promote resilience would provide insight into disease mechanisms and nominate potential targets for therapeutic intervention. Here, we use transcriptome profiling to identify gene networks present in the pre-symptomatic AD mouse brain relating to neuroinflammation, brain vasculature, extracellular matrix organization, and synaptic signaling that predict cognitive performance at an advanced age. We highlight putative drivers of these observed relationships, including Itgb2, Fcgr2b, Slc6a14, and Gper1, which represent prime targets through which to promote resilience prior to overt symptom onset. In addition, we identify a genomic region on chromosome 2 containing variants that directly modulate resilience network expression. Overall, work here highlights new potential drivers of resilience to AD and contributes significantly to our understanding of early, potentially causal, disease mechanisms.

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Citations

Aug 24, 2019·Neurobiology of Learning and Memory·Amy R Dunn, Catherine C Kaczorowski
Jan 21, 2021·Cell Systems·David G AshbrookRobert W Williams
Feb 9, 2021·Frontiers in Aging Neuroscience·Joseph A McQuailThomas C Foster
Feb 13, 2020·Cell Reports·Isabel CastanhoJonathan Mill

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Datasets Mentioned

BETA
GSE101144
GSE119215

Methods Mentioned

BETA
transgenic
RNA-seq

Software Mentioned

ComBat
AD
AMP
R
DESeq2
FreezeFrame
Bowtie
WGCNA
GOenrichmentAnalysis
GSEA

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