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| Status |
Public on Apr 19, 2021 |
| Title |
Neuronal ApoE Upregulates MHC-I Expression to Drive Selective Neurodegeneration in Alzheimer’s Disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish while others remain resilient are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that apoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of apoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between apoE expression, neuronal MHC-I expression, Tau pathology, and neurodegeneration. Functional reduction of MHC-I ameliorated Tau pathology in apoE4-expressing primary neurons and in mouse hippocampi expressing pathological Tau. These findings suggest a mechanism linking neuronal apoE expression to MHC-I expression and, subsequently, to Tau pathology and selective neurodegeneration.
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| Overall design |
Single-nucleus RNA sequencing of hippocampus from human APOE3 targeted replacement mice at 5, 10, 15, and 20 months, human APOE4 targeted replacement mice at 5, 10, 15, and 20 months, and neuron-specific APOE-KO (Syn-cre x floxed APOE) mice at 10 and 15 months.
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| Contributor(s) |
Zalocusky K, Najm R, Taubes A, Hao Y, Yoon S, Huang Y |
| Citation(s) |
33958804 |
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| Submission date |
Feb 25, 2021 |
| Last update date |
May 10, 2021 |
| Contact name |
Kelly Zalocusky |
| Organization name |
Gladstone Institutes
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| Street address |
1650 Owens Street, Gladstone Center for Translational Advancement
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| City |
San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94158 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (34)
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| Relations |
| BioProject |
PRJNA704819 |
| SRA |
SRP308158 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE167497_RAW.tar |
809.1 Mb |
(http)(custom) |
TAR (of H5) |
| GSE167497_barcode_summary_h5.h5 |
607.8 Mb |
(ftp)(http) |
H5 |
| GSE167497_filtered_gene_bc_matrices_h5.h5 |
11.7 Mb |
(ftp)(http) |
H5 |
| GSE167497_raw_gene_bc_matrices_h5.h5 |
24.2 Mb |
(ftp)(http) |
H5 |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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