1. Selective Neuronal Vulnerability in Alzheimer's Disease: A Network-Based Analysis.
- Author
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Roussarie JP, 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, and Greengard P
- Subjects
- Aging genetics, Aging pathology, Alzheimer Disease genetics, Animals, Gene Regulatory Networks physiology, Humans, Mice, Alzheimer Disease pathology, Gene Expression Profiling methods, Machine Learning, Neurons pathology, Transcriptome
- Abstract
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., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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