Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis
Jean-Pierre Roussarie, Vicky Yao, Patricia Rodriguez‐Rodriguez, Rose Oughtred, Jennifer Rust, Zakary Plautz, Shirin Kasturia, Christian A. Albornoz, Wei Wang, Eric F. Schmidt, Ruth Dannenfelser, Alicja Tadych, Lars Brichta, Alona O. Barnea-Cramer, Nathaniel Heintz, Patrick R. Hof, Myriam Heiman, Kara Dolinski, Marc Flajolet, Olga G. Troyanskaya, Paul Greengard
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.