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Genome Med. 2018 Mar 29;10(1):26. doi: 10.1186/s13073-018-0530-9.

Integrated biology approach reveals molecular and pathological interactions among Alzheimer's Aβ42, Tau, TREM2, and TYROBP in Drosophila models.

Author information

1
Department of Alzheimer's Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan.
2
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, Room 8-111, Box 1498, New York, NY, 10029, USA.
3
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA.
4
Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Japan.
5
Department of Neurology, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Center for translational & Computational Neuroimmunology, Department of Neurology, The Neurological Institute of New York, Columbia University Medical Center, New York, NY, USA.
8
Broad Institute, Cambridge, MA, USA.
9
Rush Alzheimer's Disease Research Center and Department of Neurology, Rush University Medical Center, 1750 W. Congress Parkway, Chicago, IL, 60612, USA.
10
Department of Psychiatry and Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Center for NFL Neurological Care, Department of Neurology, New York, NY, USA.
12
James J. Peters VA Medical Center, 130 West Kingsbridge Road, New York, NY, USA.
13
Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Tokyo, Japan.
14
Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, Room 8-111, Box 1498, New York, NY, 10029, USA. bin.zhang@mssm.edu.
15
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. bin.zhang@mssm.edu.
16
Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, New York, NY, USA. bin.zhang@mssm.edu.
17
Department of Alzheimer's Disease Research, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan. iijimakm@ncgg.go.jp.
18
Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Japan. iijimakm@ncgg.go.jp.

Abstract

BACKGROUND:

Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer's disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP.

METHODS:

In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts.

RESULTS:

Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD.

CONCLUSIONS:

The comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies.

KEYWORDS:

Alzheimer’s disease; Amyloid-β (Aβ) peptides; Differential expression; Gene co-expression network; Gene module; Immune function; Microtubule-associated protein tau; Neurodegeneration; Synaptophagy; TREM2 (triggering receptor expressed on myeloid cells 2); TYROBP (tyrosine kinase binding protein)

PMID:
29598827
PMCID:
PMC5875009
DOI:
10.1186/s13073-018-0530-9
[Indexed for MEDLINE]
Free PMC Article

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