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
JournalNeuron
Date Published2020 Jun 24
ISSN1097-4199
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.

DOI10.1016/j.neuron.2020.06.010
Alternate JournalNeuron
PubMed ID32603655