Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease.

Aged Aged, 80 and over Alzheimer Disease / etiology Amyloid beta-Peptides / metabolism Animals Brain / pathology Datasets as Topic Disease Models, Animal Female Gene Expression Profiling Gene Regulatory Networks Genome-Wide Association Study Humans Male Mice Mice, Transgenic Nerve Growth Factors / genetics Protein Interaction Mapping Protein Interaction Maps Proteomics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
07 08 2020
Historique:
received: 23 08 2019
accepted: 15 06 2020
entrez: 10 8 2020
pubmed: 10 8 2020
medline: 22 9 2020
Statut: epublish

Résumé

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.

Identifiants

DOI: 10.1038/s41467-020-17405-z PMID: 32770063 PMC: PMC7414858
pubmed: 32770063
doi: 10.1038/s41467-020-17405-z
pii: 10.1038/s41467-020-17405-z
pmc: PMC7414858
doi:

Substances chimiques

Amyloid beta-Peptides 0
Nerve Growth Factors 0
VGF protein, human 0
Vgf protein, mouse 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3942

Subventions

Organisme : NINDS NIH HHS
ID : P30 NS055077
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067312
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG062661
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046161
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117504
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046170
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059319
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057443
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG053960
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA210993
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG055501
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG025688
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066514
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054014
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057907
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062355
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057440
Pays : United States

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Auteurs

Noam D Beckmann (ND)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Wei-Jye Lin (WJ)

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China.
Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Minghui Wang (M)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
ORCID: 0000-0001-9171-4962

Ariella T Cohain (AT)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Alexander W Charney (AW)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Pei Wang (P)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
ORCID: 0000-0002-6890-6453

Weiping Ma (W)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Ying-Chih Wang (YC)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Cheng Jiang (C)

Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
ORCID: 0000-0003-4583-3295

Mickael Audrain (M)

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
ORCID: 0000-0001-9941-7380

Phillip H Comella (PH)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Amanda K Fakira (AK)

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Siddharth P Hariharan (SP)

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
ORCID: 0000-0003-1814-6457

Gillian M Belbin (GM)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Kiran Girdhar (K)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Allan I Levey (AI)

Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
ORCID: 0000-0002-3153-502X

Nicholas T Seyfried (NT)

Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
ORCID: 0000-0002-4507-624X

Eric B Dammer (EB)

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
ORCID: 0000-0003-2947-7606

Duc Duong (D)

Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.

James J Lah (JJ)

Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.

Jean-Vianney Haure-Mirande (JV)

Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
ORCID: 0000-0002-5748-9666

Ben Shackleton (B)

Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Tomas Fanutza (T)

Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
ORCID: 0000-0002-2563-9121

Robert Blitzer (R)

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Eimear Kenny (E)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Jun Zhu (J)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Sema4, Stamford, CT, 06902, USA.
ORCID: 0000-0003-0834-8178

Vahram Haroutunian (V)

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.
ORCID: 0000-0001-5860-2512

Pavel Katsel (P)

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.

Sam Gandy (S)

Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.

Zhidong Tu (Z)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Michelle E Ehrlich (ME)

Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Bin Zhang (B)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Stephen R Salton (SR)

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. stephen.salton@mssm.edu.
Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. stephen.salton@mssm.edu.
ORCID: 0000-0003-4087-8427

Eric E Schadt (EE)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. eric.schadt@mssm.edu.
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. eric.schadt@mssm.edu.
Sema4, Stamford, CT, 06902, USA. eric.schadt@mssm.edu.
ORCID: 0000-0002-7892-8808

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Peptides bêta-amyloïdes › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Eucaryotes › Animaux › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Jeux de données comme sujet › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de profil d'expression de gènes › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Séquences d'acides nucléiques régulatrices › Réseaux de régulation génique › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Facteurs de croissance nerveuse › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Techniques d'investigation › Techniques de sonde moléculaire › Cartographie d'interactions entre protéines › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Cartes d'interactions protéiques › Multiscale causal networks identify VGF as a...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Multiscale causal networks identify VGF as a...