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RNA-seq of primary tumors from Braf/Pten/Cre APOE2 and APOE4 mice

ABSTRACT: Genetic variation in the APOE gene modulates melanoma progression. To identify tumor cell-intrinsic mechanisms underlying differences in tumor progression between APOE2 and APOE4 genotypes, we crossed the Braf/Pten/Cre (BPC) genetically engineered mouse model with APOE2 (BPCE2) and APOE4 (BPCE4) knock-in mice. We performed RNA-Seq on tumors derived from these mice. This analysis revealed protein synthesis as a process that is enhanced by APOE2. **Note: Raw fastq sequencing files for these samples were irrevocably corrupted due to a server failure and therefore could not be provided. Kallisto transcript abundance estimates have been included as processed data.**

ORGANISM(S): Mus musculus

PROVIDER: GSE209873 | GEO | 2023/06/09

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The APOE ε2 encoding apolipoprotein E (APOE2) is a protective allele against AD among the three genotypes (APOE ε2, ε3, ε4), while APOE4 is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where APOE2 has a superior function compared to APOE3 and APOE4. Gene therapy that increases APOE2 levels in the brain is, therefore, a promising therapeutic strategy for AD treatment. We previously reported that PEGylated liposomes conjugated with transferrin and a cell-penetrating peptide Penetratin sufficiently deliver chitosan-APOE2 cDNA plasmid complex into the brain of wild-type mice. Here, we investigated how brain-targeting liposome-based APOE2 gene delivery influences Aβ)-related pathologies in amyloid model AppNL-G-F knockin mice at 12-month-old. We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after APOE2 gene therapy. Furthermore, in the AppNL-G-F knockin mice that received the APOE2 gene therapy, brain transcriptome analysis through RNA-sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of Dlg4 and Syp mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that APOE2 gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin. Together, our results suggest that brain-targeting liposome-based APOE2 gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced APOE2 expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.

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RNA-seq of primary tumors from Braf/Pten/Cre APOE2 and APOE4 mice

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