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Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

View ORCID ProfileJean-Pierre Roussarie, Victoria Yao, Zakary Plautz, Shirin Kasturia, Christian Albornoz, Eric F Schmidt, Lars Brichta, Alona Barnea-Cramer, Nathaniel Heintz, Patrick Hof, Myriam Heiman, Marc Flajolet, Olga Troyanskaya, Paul Greengard
doi: https://doi.org/10.1101/499897
Jean-Pierre Roussarie
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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  • ORCID record for Jean-Pierre Roussarie
  • For correspondence: greengard@mail.rockefeller.edu ogt@cs.princeton.edu jroussarie@rockefeller.edu
Victoria Yao
2Department of Computer Science, Princeton University
3Lewis-Sigler Institute for Integrative Genomics, Princeton University
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Zakary Plautz
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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Shirin Kasturia
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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Christian Albornoz
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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Eric F Schmidt
4Laboratory of Molecular Biology, The Rockefeller University
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Lars Brichta
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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Alona Barnea-Cramer
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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Nathaniel Heintz
4Laboratory of Molecular Biology, The Rockefeller University
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Patrick Hof
5Icahn School of Medicine at Mount Sinai
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Myriam Heiman
6Broad Institute of MIT and Harvard
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Marc Flajolet
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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Olga Troyanskaya
2Department of Computer Science, Princeton University
3Lewis-Sigler Institute for Integrative Genomics, Princeton University
7Flatiron Institute, Simons Foundation
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  • For correspondence: greengard@mail.rockefeller.edu ogt@cs.princeton.edu jroussarie@rockefeller.edu
Paul Greengard
1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University
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  • For correspondence: greengard@mail.rockefeller.edu ogt@cs.princeton.edu jroussarie@rockefeller.edu
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Abstract

A major obstacle to treating Alzheimer’s disease (AD) is our lack of understanding of the molecular mechanisms underlying selective neuronal vulnerability, which is a key characteristic of the disease. Here we present a framework to integrate 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 AD vulnerable and resistant neurons, identify specific genes and pathways associated with AD pathology, and pinpoint a specific functional gene module underlying selective vulnerability, enriched in processes associated with axonal remodeling, and affected by both amyloid accumulation and aging. Overall, our study provides a molecular framework for understanding the complex interplay between Aβ, aging, and neurodegeneration within the most vulnerable neurons in AD.

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Posted December 19, 2018.
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Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis
Jean-Pierre Roussarie, Victoria Yao, Zakary Plautz, Shirin Kasturia, Christian Albornoz, Eric F Schmidt, Lars Brichta, Alona Barnea-Cramer, Nathaniel Heintz, Patrick Hof, Myriam Heiman, Marc Flajolet, Olga Troyanskaya, Paul Greengard
bioRxiv 499897; doi: https://doi.org/10.1101/499897
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Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis
Jean-Pierre Roussarie, Victoria Yao, Zakary Plautz, Shirin Kasturia, Christian Albornoz, Eric F Schmidt, Lars Brichta, Alona Barnea-Cramer, Nathaniel Heintz, Patrick Hof, Myriam Heiman, Marc Flajolet, Olga Troyanskaya, Paul Greengard
bioRxiv 499897; doi: https://doi.org/10.1101/499897

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