Dysregulated Fc gamma receptor-mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis

Young Ho Park; Angela Hodges; Shannon L Risacher; Kuang Lin; Jae-Won Jang; Soyeon Ahn; SangYun Kim; Simon Lovestone; Andrew Simmons; Michael W Weiner; Andrew J Saykin; Kwangsik Nho; AddNeuroMed consortium and the Alzheimer's Disease Neuroimaging Initiative

doi:10.1016/j.neurobiolaging.2019.12.001

Dysregulated Fc gamma receptor-mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis

Neurobiol Aging. 2020 Apr:88:24-32. doi: 10.1016/j.neurobiolaging.2019.12.001. Epub 2019 Dec 10.

Affiliations

¹ Department of Radiology and Imaging Sciences, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, Republic of Korea.
² Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
³ Department of Radiology and Imaging Sciences, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
⁴ Department of Neurology, Kangwon National University Hospital, Chuncheon, Republic of Korea.
⁵ Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
⁶ Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, Republic of Korea.
⁷ Department of Psychiatry, University of Oxford, Oxford, UK.
⁸ Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, CA, USA; Department of Veterans Affairs Medical Center, San Francisco, CA, USA.
⁹ Department of Radiology and Imaging Sciences, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: asaykin@iu.edu.
¹⁰ Department of Radiology and Imaging Sciences, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: knho@iu.edu.

PMID: 31901293
PMCID: PMC7085455
DOI: 10.1016/j.neurobiolaging.2019.12.001

Abstract

Transcriptomics has become an important tool for identification of biological pathways dysregulated in Alzheimer's disease (AD). We performed a network-based gene expression analysis of blood-based microarray gene expression profiles using 2 independent cohorts, Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 661) and AddNeuroMed (N = 674). Weighted gene coexpression network analysis identified 17 modules from ADNI and 13 from AddNeuroMed. Four of the modules derived in ADNI were significantly related to AD; 5 modules in AddNeuroMed were significant. Gene-set enrichment analysis of the AD-related modules identified and replicated 3 biological pathways including the Fc gamma receptor-mediated phagocytosis pathway. Module-based association analysis showed the AD-related module, which has the 3 pathways, to be associated with cognitive function and neuroimaging biomarkers. Gene-based association analysis identified PRKCD in the Fc gamma receptor-mediated phagocytosis pathway as being significantly associated with cognitive function and cerebrospinal fluid biomarkers. The identification of the Fc gamma receptor-mediated phagocytosis pathway implicates the peripheral innate immune system in the pathophysiology of AD. PRKCD is known to be related to neurodegeneration induced by amyloid-β.

Keywords: Alzheimer's disease; Coexpression; Network; PRKCD; Phagocytosis; Transcriptome.

Publication types

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

MeSH terms

Alzheimer Disease / genetics*
Alzheimer Disease / immunology
Alzheimer Disease / psychology
Amyloid beta-Peptides / metabolism
Cognition
Gene Expression Profiling / methods*
Gene Expression*
Genetic Association Studies*
Immunity, Innate
Phagocytosis / genetics*
Protein Kinase C-delta*
Receptors, IgG / genetics*
Receptors, IgG / physiology*
Signal Transduction / genetics*
Signal Transduction / physiology*
Transcriptome / genetics*

Substances

Amyloid beta-Peptides
Receptors, IgG
PRKCD protein, human
Protein Kinase C-delta

Dysregulated Fc gamma receptor-mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis

Authors

Affiliations

Abstract

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MeSH terms

Substances

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