Selective Neuronal Vulnerability in Alzheimer's Disease: A Network-Based Analysis.

TitleSelective Neuronal Vulnerability in Alzheimer's Disease: A Network-Based Analysis.
Publication TypeJournal Article
Year of Publication2020
AuthorsRoussarie, 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
Date Published2020 Sep 09
KeywordsAging, Alzheimer Disease, Animals, Gene Expression Profiling, Gene Regulatory Networks, Humans, Machine Learning, Mice, Neurons, Transcriptome

<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 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>

Alternate JournalNeuron
PubMed ID32603655
PubMed Central IDPMC7580783
Grant ListR01 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