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Neuron. 2018 Jul 11;99(1):64-82.e7. doi: 10.1016/j.neuron.2018.05.023. Epub 2018 Jun 21.

Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus.

Author information

1
Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287-5001, USA.
2
Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Institute for Systems Biology, Seattle, WA, 98109-5263, USA.
4
Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY 10468, USA.
5
James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY 10468, USA; Department of Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
Arizona Alzheimer's Consortium, Phoenix, AZ 85014, USA; Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
7
Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Arizona Alzheimer's Consortium, Phoenix, AZ 85014, USA; Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA; Department of Psychiatry, University of Arizona, Phoenix, AZ 85721, USA; Banner Alzheimer's Institute, Phoenix, AZ 85006, USA.
9
Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Sema4, Stamford, CT 06902, USA.
10
Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
11
Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY 10468, USA; Department of Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for NFL Neurological Care, Department of Neurology, New York, NY 10029, USA.
12
Departments of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute of Genomic Sciences and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Next Generation Healthcare, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287-5001, USA. Electronic address: joel.dudley@mssm.edu.

Abstract

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.

KEYWORDS:

Alzheimer's disease; HHV-6A; HHV-6B; HHV-7; Roseolovirus; human herpesvirus; integrative genomics; multiscale networks; network biology; systems biology

PMID:
29937276
PMCID:
PMC6551233
DOI:
10.1016/j.neuron.2018.05.023
[Indexed for MEDLINE]
Free PMC Article

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