PMID- 29937276
OWN - NLM
STAT- MEDLINE
DCOM- 20190730
LR  - 20231012
IS  - 1097-4199 (Electronic)
IS  - 0896-6273 (Print)
IS  - 0896-6273 (Linking)
VI  - 99
IP  - 1
DP  - 2018 Jul 11
TI  - Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of 
      Molecular, Genetic, and Clinical Networks by Human Herpesvirus.
PG  - 64-82.e7
LID - S0896-6273(18)30421-5 [pii]
LID - 10.1016/j.neuron.2018.05.023 [doi]
AB  - 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.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Readhead, Ben
AU  - Readhead B
AD  - 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.
FAU - Haure-Mirande, Jean-Vianney
AU  - Haure-Mirande JV
AD  - Department of Neurology, Alzheimer's Disease Research Center, Icahn School of 
      Medicine at Mount Sinai, New York, NY 10029, USA.
FAU - Funk, Cory C
AU  - Funk CC
AD  - Institute for Systems Biology, Seattle, WA, 98109-5263, USA.
FAU - Richards, Matthew A
AU  - Richards MA
AD  - Institute for Systems Biology, Seattle, WA, 98109-5263, USA.
FAU - Shannon, Paul
AU  - Shannon P
AD  - Institute for Systems Biology, Seattle, WA, 98109-5263, USA.
FAU - Haroutunian, Vahram
AU  - Haroutunian V
AD  - 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.
FAU - Sano, Mary
AU  - Sano M
AD  - 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.
FAU - Liang, Winnie S
AU  - Liang WS
AD  - Arizona Alzheimer's Consortium, Phoenix, AZ 85014, USA; Neurogenomics Division, 
      Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
FAU - Beckmann, Noam D
AU  - Beckmann ND
AD  - 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.
FAU - Price, Nathan D
AU  - Price ND
AD  - Institute for Systems Biology, Seattle, WA, 98109-5263, USA.
FAU - Reiman, Eric M
AU  - Reiman EM
AD  - 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.
FAU - Schadt, Eric E
AU  - Schadt EE
AD  - 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.
FAU - Ehrlich, Michelle E
AU  - Ehrlich ME
AD  - 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.
FAU - Gandy, Sam
AU  - Gandy S
AD  - 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.
FAU - Dudley, Joel T
AU  - Dudley JT
AD  - 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.
LA  - eng
GR  - RF1 AG058469/AG/NIA NIH HHS/United States
GR  - U01 AG046152/AG/NIA NIH HHS/United States
GR  - RF1 AG015819/AG/NIA NIH HHS/United States
GR  - U54 EB020406/EB/NIBIB NIH HHS/United States
GR  - P50 AG016574/AG/NIA NIH HHS/United States
GR  - P30 AG010161/AG/NIA NIH HHS/United States
GR  - R01 AG032990/AG/NIA NIH HHS/United States
GR  - R01 NS080820/NS/NINDS NIH HHS/United States
GR  - U01 AG046139/AG/NIA NIH HHS/United States
GR  - P01 AG017216/AG/NIA NIH HHS/United States
GR  - R01 AG018023/AG/NIA NIH HHS/United States
GR  - R56 AG058469/AG/NIA NIH HHS/United States
GR  - U01 AG032984/AG/NIA NIH HHS/United States
GR  - R01 AG030146/AG/NIA NIH HHS/United States
GR  - U01 AG046170/AG/NIA NIH HHS/United States
GR  - R01 AG017917/AG/NIA NIH HHS/United States
GR  - R34 AG049649/AG/NIA NIH HHS/United States
GR  - P01 AG003949/AG/NIA NIH HHS/United States
GR  - U24 NS072026/NS/NINDS NIH HHS/United States
GR  - P30 AG019610/AG/NIA NIH HHS/United States
GR  - P50 AG025711/AG/NIA NIH HHS/United States
GR  - U01 AG006786/AG/NIA NIH HHS/United States
GR  - R01 AG036836/AG/NIA NIH HHS/United States
GR  - R01 AG015819/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180621
PL  - United States
TA  - Neuron
JT  - Neuron
JID - 8809320
RN  - 0 (APBB2 protein, human)
RN  - 0 (APP protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (BIN1 protein, human)
RN  - 0 (CLU protein, human)
RN  - 0 (Clusterin)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn155 microRNA, mouse)
RN  - 0 (Monomeric Clathrin Assembly Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (PICALM protein, human)
RN  - 0 (PSEN1 protein, human)
RN  - 0 (Presenilin-1)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
CIN - Trends Neurosci. 2018 Sep;41(9):570-573. PMID: 30033181
CIN - Front Mol Neurosci. 2018 Sep 20;11:340. PMID: 30294260
CIN - Neuron. 2019 Dec 18;104(6):1034-1035. PMID: 31855626
CIN - Neuron. 2019 Dec 18;104(6):1036-1037. PMID: 31855627
CIN - J Bioinform Comput Biol. 2020 Feb;18(1):2050012. PMID: 32336252
MH  - Adaptor Proteins, Signal Transducing/genetics
MH  - Alzheimer Disease/genetics/metabolism/pathology/*virology
MH  - Amyloid Precursor Protein Secretases/genetics
MH  - Amyloid beta-Protein Precursor/*metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/genetics
MH  - Brain/metabolism/pathology/*virology
MH  - Case-Control Studies
MH  - Clusterin/genetics
MH  - Cohort Studies
MH  - Encephalitis, Viral/genetics/metabolism/pathology/*virology
MH  - Gene Expression Profiling
MH  - Gene Regulatory Networks
MH  - Genomics
MH  - *Herpesvirus 6, Human
MH  - *Herpesvirus 7, Human
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - MicroRNAs/genetics
MH  - Microbiota
MH  - Monomeric Clathrin Assembly Proteins/genetics
MH  - Nuclear Proteins/genetics
MH  - Presenilin-1/genetics
MH  - Proteomics
MH  - Roseolovirus Infections/genetics/metabolism/pathology/*virology
MH  - Tumor Suppressor Proteins/genetics
MH  - Viral Load
PMC - PMC6551233
MID - NIHMS975797
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - HHV-6A
OT  - HHV-6B
OT  - HHV-7
OT  - Roseolovirus
OT  - human herpesvirus
OT  - integrative genomics
OT  - multiscale networks
OT  - network biology
OT  - systems biology
COIS- Declarations of Interests The authors declare that they have no competing 
      financial interests in relation to the work described.
EDAT- 2018/06/26 06:00
MHDA- 2019/07/31 06:00
PMCR- 2019/07/11
CRDT- 2018/06/26 06:00
PHST- 2017/12/12 00:00 [received]
PHST- 2018/03/05 00:00 [revised]
PHST- 2018/05/15 00:00 [accepted]
PHST- 2018/06/26 06:00 [pubmed]
PHST- 2019/07/31 06:00 [medline]
PHST- 2018/06/26 06:00 [entrez]
PHST- 2019/07/11 00:00 [pmc-release]
AID - S0896-6273(18)30421-5 [pii]
AID - 10.1016/j.neuron.2018.05.023 [doi]
PST - ppublish
SO  - Neuron. 2018 Jul 11;99(1):64-82.e7. doi: 10.1016/j.neuron.2018.05.023. Epub 2018 
      Jun 21.