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| Status |
Public on Apr 05, 2020 |
| Title |
Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from individuals spanning the neuropathological progression of AD. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.
The brain tissue used in this study were sourced from the Biobank for Aging Studies (LIM-22) in the Department of Pathology at the University of Sao Paulo, as well as from the Neurodegenerative Diseases Brain Bank in the Memory and Aging Center at the University of California, San Francisco. Detailed neuropathological, clinical and genetic data are available under request. Please contact gerolab@gmail.com and lea.grinberg@ucsf.edu.
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| Overall design |
Single-nucleus RNA-sequencing of post-mortem brain tissue from donors spanning the range of AD progression.
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| Contributor(s) |
Leng K, Kampmann M, Grinberg L |
| Citation(s) |
33432193 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R56 AG057528 |
Uncovering mechanisms of selective vulnerability by CRISPR-based genetic screens |
University of California San Francisco |
Lea Tenenholz Grinberg |
| R56 AG057528 |
Uncovering mechanisms of selective vulnerability by CRISPR-based genetic screens |
University of California San Francisco |
Martin Kampmann |
| K24 AG053435 |
Neuropathological changes underlying clinical heterogeneity in Alzheimer disease |
University of California San Francisco |
Lea Tenenholz Grinberg |
| U54 NS100717 |
Linking tau proteostasis with neuronal activity in FTD |
WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY |
Li Gan |
| F30 AG066418 |
Elucidating cellular pathways controlling the reactive state of astrocytes in Alzheimer?s Disease |
University of California San Francisco |
Kun Leng |
|
| Submission date |
Mar 25, 2020 |
| Last update date |
Apr 25, 2022 |
| Contact name |
Kun Leng |
| E-mail(s) |
kun.leng@ucsf.edu
|
| Organization name |
University of California San Francisco
|
| Department |
Institute for Neurodegenerative Diseases
|
| Street address |
675 Nelson Rising Lane, 3rd Floor
|
| City |
San Francisco |
| State/province |
Calfironia |
| ZIP/Postal code |
94158 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (20)
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| Relations |
| BioProject |
PRJNA615180 |
| SRA |
SRP254025 |
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