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| 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
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| 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.
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| 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.
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| 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 |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Oct 28, 2021 |
| Last update date |
Oct 02, 2023 |
| Contact name |
Samuel Hildebrand |
| E-mail(s) |
samuel.hildebrand@umassmed.edu
|
| Organization name |
University of Massachusetts Medical School
|
| Department |
RNA Therapeutics Institute
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| Lab |
Khvorova
|
| Street address |
368 Plantation Street
|
| City |
Worcester |
| State/province |
MA |
| ZIP/Postal code |
01605 |
| Country |
USA |
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| Platforms (1) |
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| Samples (89)
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| Relations |
| BioProject |
PRJNA775977 |
| SRA |
SRP343627 |
| 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 |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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