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| Status |
Public on Aug 05, 2020 |
| Title |
Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tau aggregation in neurofibrillary tangles (NFTs) is closely associated with neurodegeneration and cognitive decline in Alzheimer’s disease (AD). However, the molecular signatures that distinguish between aggregation-prone and aggregation-resistant cell states are unknown. We developed methods for the high-throughput isolation and transcriptome profiling of single somas with NFTs fro¬m human AD brain, quantified the susceptibility of 20 neocortical subtypes for NFT formation and death, and identified both shared and cell-type-specific signatures. NFT-bearing neurons shared a marked upregulation of synaptic transmission-related genes, including a core set of 63 genes enriched for synaptic vesicle cycling. Oxidative phosphorylation and mitochondrial dysfunction were highly cell-type dependent. Apoptosis was only modestly enriched, and the susceptibilities of NFT-bearing and NFT-free neurons for death were highly similar. Our analysis suggests that NFTs represent cell-type-specific responses to stress and synaptic dysfunction. We provide a resource for biomarker discovery and the investigation of tau-dependent and tau-independent mechanisms of neurodegeneration.
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| Overall design |
Fresh frozen brain tissue from the prefrontal cortex (BA9) of eight Braak stage VI AD and eight age-matched healthy control donors was micro-dissected and dissociated without detergents or enzymatic digestion. Immunostaining and FACS using an antibody to detect pathological tau aggregates (AT8) and the pan-neuronal marker MAP2 was used to isolate somas with NFTs (n = 24,660) and neighboring NFT-free neurons (n = 38,465) from AD donors and control NFT-free somas (n = 63,110). RNA capture and library preparation was performed using the 10× Genomics Chromium Single Cell 3’ v2 or v3 assay. The generated paired-end libraries were sequenced on Illumina Novaseq 6000. Paired-end sequence reads were processed using the 10× Genomics software package Cell Ranger and the R-based Seurat package. Raw data is available in SRA with Study accession SRP189891 and Bioproject accession PRJNA528824.
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| Web link |
https://doi.org/10.1016/j.neuron.2022.06.021
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| Contributor(s) |
Otero-Garcia M, Xue Y, Shakouri T, Deng Y, Morabito S, Kawaguchi R, Swarup V, Cobos I |
| Citation |
Marcos Otero-Garcia, Yue-Qiang Xue, Tamara Shakouri, Yongning Deng, Samuel Morabito, Thomas Allison, William E. Lowry, Riki Kawaguchi, Vivek Swarup, Inma Cobos. Single-soma transcriptomics of tangle-bearing neurons in Alzheimer's disease reveals the signatures of tau-associated synaptic dysfunction. bioRxiv 2020.05.11.088591; doi:10.1101/2020.05.11.088591.
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| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 AG059848 |
Resolving selective vulnerability and disease progression in human Alzheimer's brain via single-cell RNA-seq |
STANFORD UNIVERSITY |
Maria Inmaculada Cobos Sillero |
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| Submission date |
Apr 03, 2019 |
| Last update date |
Nov 29, 2022 |
| Contact name |
Inma Cobos |
| E-mail(s) |
icobos@stanford.edu
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| Phone |
6507258200
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| Organization name |
STANFORD UNIVERSITY MEDICAL SCHOOL
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| Street address |
300 Pasteur Drive, Lane Building, L235
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| City |
Stanford |
| State/province |
California |
| ZIP/Postal code |
94305-5324 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (27)
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| Relations |
| BioProject |
PRJNA530780 |
| SRA |
SRP190819 |
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