Transcriptomics,Genomics

Dataset Information

42

Transcriptomic analysis of the effect of ASO-mediated CD33 knock-down on the microglial gene network in an APP/PS1 mouse model of Alzheimer’s disease. [LNA-006]


ABSTRACT: Microglia, the resident innate immune cells of the central nervous system (CNS), are increasingly recognized as critical for normal CNS function as well as for the pathophysiology of CNS disorders, including Alzheimer's disease (AD). Advances in transcriptomic analyses, such as weighted gene co-expression network analysis, reveal that the most perturbed gene networks identified in AD brains fall squarely within microglial pathways and these findings are consistent with genetic and epigenetic genome-wide association studies linking specific microglial genes to AD risk. Increased expression of full-length CD33 increases AD risk and CD33 is a component of the microglial gene network, yet relatively little is known about the significance of CD33 in this gene network or in microglial biology. To gain further insight into these questions, we first identified and characterized locked nucleic acid (LNA) antisense oligonucleotides (ASOs) as tools to knock down CD33 in APP/PS1 mice in vivo. We report here that CD33 LNA ASO results in robust knockdown of CD33 mRNA the frontal cortex and hippocampus of APP/PS1 mice and that this knockdown causes changes to the AD-associated microglial gene network. This work suggests that CD33 may be a viable therapeutic target in AD. Overall design: The double transgenic APP/PS1 mouse model of AD (first described by Mathias Jucker’s group) was treated either with a CD33-specific ASO (N=10), a non-target Control ASO (N=10), or PBS vehicle (N=10). Wild-type littermates were also treated with PBS vehicle (N=10). Animals were dosed with 75ug/day of ASO (pump delivered 6uL/day) for 14 days starting at 18 weeks of age and were sacrificed at ~20.5 weeks of age (~ 17 days after start of 14 day ASO infusion). N for microarray analysis is as follows: For Hippocampus, APP/PS1_ CD33 ASO, n=9; APP/PS1_CON ASO, n=11; APP/PS1_PBS, n=8; WT_PBS, n=11; and for frontal cortex, APP/PS1_ CD33 ASO, n=10; APP/PS1_CON ASO, n=11; APP/PS1_PBS, n=8; WT_PBS, n=11.

INSTRUMENT(S): Illumina MouseRef-8 v2.0 expression beadchip

SUBMITTER: Mary E Hamby  

PROVIDER: GSE74437 | GEO | 2016-09-30

SECONDARY ACCESSION(S): PRJNA300426

REPOSITORIES: GEO

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