Title | Selective Neuronal Vulnerability in Alzheimer's Disease: A Network-Based Analysis. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Roussarie, J-P, Yao, V, Rodriguez-Rodriguez, P, Oughtred, R, Rust, J, Plautz, Z, Kasturia, S, Albornoz, C, Wang, W, Schmidt, EF, Dannenfelser, R, Tadych, A, Brichta, L, Barnea-Cramer, A, Heintz, N, Hof, PR, Heiman, M, Dolinski, K, Flajolet, M, Troyanskaya, OG, Greengard, P |
Journal | Neuron |
Volume | 107 |
Issue | 5 |
Pagination | 821-835.e12 |
Date Published | 2020 Sep 09 |
ISSN | 1097-4199 |
Keywords | Aging, Alzheimer Disease, Animals, Gene Expression Profiling, Gene Regulatory Networks, Humans, Machine Learning, Mice, Neurons, Transcriptome |
Abstract | <p>A major obstacle to treating Alzheimer's disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, a key characteristic of the disease. Here, we present a framework integrating high-quality neuron-type-specific molecular profiles across the lifetime of the healthy mouse, which we generated using bacTRAP, with postmortem human functional genomics and quantitative genetics data. We demonstrate human-mouse conservation of cellular taxonomy at the molecular level for neurons vulnerable and resistant in AD, identify specific genes and pathways associated with AD neuropathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by amyloid accumulation and aging. We have made all cell-type-specific profiles and functional networks available at http://alz.princeton.edu. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.</p> |
DOI | 10.1016/j.neuron.2020.06.010 |
Alternate Journal | Neuron |
PubMed ID | 32603655 |
PubMed Central ID | PMC7580783 |
Grant List | R01 OD010929 / OD / NIH HHS / United States RF1 AG047779 / AG / NIA NIH HHS / United States RF1 AG054564 / AG / NIA NIH HHS / United States R01 GM071966 / GM / NIGMS NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States R01 NS091722 / NS / NINDS NIH HHS / United States T32 HG003284 / HG / NHGRI NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States |