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Series GSE186756 Query DataSets for GSE186756
Status Public on Oct 02, 2023
Title mRNA sequencing of brain and liver in multiple Alzheimer's Disease mouse models after treatment with either a Non-Targeting Control siRNA or an siRNA targeting mouse Apoe mRNA
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary The most common genetic risk factor for late onset Alzheimer Disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function as a primary mechanism. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due to the role of liver ApoE in cholesterol homeostasis. Previous attempts to therapeutically block brain-specific ApoE in adult models of AD only modestly reduced ApoE expression and no significant impact on amyloid burden. Here, we optimized a divalent siRNA (di-siRNA) to selectively silence ApoE in brain (>2 months). By measuring transcriptomic changes upon knockdown of ApoE in the CNS in multiple mouse models of AD, we find that ApoE knockdown results in an upregulation of the innate immune response, likely through activation of microglia. Additionally, we find that the changes in the transcriptome were similar, but not identical, two weeks and two months post-treatment. We find that mild reduction of ApoE in the liver does not cause widespread transcriptomic changes, but near complete knockdown of ApoE in the liver results in the dysregulation of many lipid metabolism-related pathways.
Overall design For the brain samples in each mouse model and each treatment (NTC or ApoE siRNA) timepoint (2 Weeks or 2 Months post-treatment) the sample size was 10-20 mice. For the liver samples in each treatment (NTC or ApoE siRNA, bilateral intracerebroventricular or subcutaneous injections) the sample size was 3-4 mice.
Contributor(s) Ferguson CM, Hildebrand SR, Godinho BM, Buchwald J, Echeverria D, Coles A, Grigorenko A, Vanjielli L, Sousa J, McHugh N, Hassler M, Meda P, Watts J, Rogaev E, Khvorova A
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Submission date Oct 28, 2021
Last update date Oct 02, 2023
Contact name Samuel Hildebrand
Organization name University of Massachusetts Medical School
Department RNA Therapeutics Institute
Lab Khvorova
Street address 368 Plantation Street
City Worcester
State/province MA
ZIP/Postal code 01605
Country USA
Platforms (1)
GPL21626 NextSeq 550 (Mus musculus)
Samples (89)
GSM5660522 5AD_NTC_2Week_F_A1
GSM5660523 5AD_NTC_2Week_F_A2
GSM5660524 5AD_NTC_2Week_F_A3
BioProject PRJNA775977
SRA SRP343627

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Supplementary file Size Download File type/resource
GSE186756_Brain_2AD_norm_counts.csv.gz 1.7 Mb (ftp)(http) CSV
GSE186756_Brain_5AD_norm_counts.csv.gz 5.4 Mb (ftp)(http) CSV
GSE186756_Dio_Liver_Conditions_2AD.csv.gz 213 b (ftp)(http) CSV
GSE186756_Extended_Data_File_11_APPPSEN1_Liver_DE_genes.csv.gz 102.7 Kb (ftp)(http) CSV
GSE186756_Extended_Data_File_7_RNAseq_Tables.xlsx 17.0 Mb (ftp)(http) XLSX
GSE186756_Extended_Data_File_8_GSEA_Results.xlsx 355.4 Kb (ftp)(http) XLSX
GSE186756_Extended_Data_File_9_WGCNA_All_Results.xlsx 16.2 Mb (ftp)(http) XLSX
GSE186756_Liver_2AD_Dio_norm_counts.csv.gz 659.4 Kb (ftp)(http) CSV
GSE186756_Liver_2AD_Gal_norm_counts.csv.gz 759.9 Kb (ftp)(http) CSV
GSE186756_conditions_Brain_2AD.csv.gz 278 b (ftp)(http) CSV
GSE186756_conditions_Brain_5AD.csv.gz 441 b (ftp)(http) CSV
GSE186756_conditions_GalNAc_Liver_2AD.csv.gz 210 b (ftp)(http) CSV
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