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

Journal: Neuron
Published Date: Jun 29, 2020

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.

Authors

  • Jean-Pierre Roussarie
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA. Electronic address: jroussarie@rockefeller.edu.
  • Vicky Yao
    Department of Computer Science, Rice University, Houston, TX 77005, USA; Department of Computer Science, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
  • Patricia Rodriguez-Rodriguez
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA; Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 171 77 Solna, Sweden.
  • Rose Oughtred
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Jennifer Rust
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Zakary Plautz
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
  • Shirin Kasturia
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
  • Christian Albornoz
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
  • Wei Wang
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.
  • Eric F Schmidt
    Laboratory of Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
  • Ruth Dannenfelser
    Department of Computer Science, Princeton University, Princeton, NJ 08544, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
  • Alicja Tadych
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
  • Lars Brichta
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
  • Alona Barnea-Cramer
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
  • Nathaniel Heintz
    Laboratory of Molecular Biology, The Rockefeller University, New York, NY 10065, USA.
  • Patrick R Hof
    Nash Family Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Myriam Heiman
    Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Kara Dolinski
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • Marc Flajolet
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
  • Olga G Troyanskaya
    Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA. ogt@cs.princeton.edu.
  • Paul Greengard
    Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.

Keywords

External Resources

Popular Topics
Recent Journals