Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila models
Year: 2018
Type: article
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.
Source: Genome Medicine
Institutions: National Center for Geriatrics and Gerontology, Icahn School of Medicine at Mount Sinai, Nagoya City University, Broad Institute, Columbia University Irving Medical Center, Columbia University, Rush University Medical Center, James J. Peters VA Medical Center, Tokyo Metropolitan University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,290
Awards: G1282666458, Integrative Network Modeling of Cognitive Resilience to Alzheimer's Disease, G1873086997, G221741096, G266544023, G268727528, Exploring the Role of the Brain Transcriptome in Cognitive Decline, G3350369400, Pathway discovery, validation and compound identification for Alzheimer's disease, G434761767, Risk Factors, Pathology, and Clinical Expressions of AD, Mechanisms underlying neuronal dysfunction and degeneration caused by loss of presynaptic mitochondria, Towards a comprehensive signaling pathway map of parahippocampal vulnerability in Alzheimers Disease, G6158664425, Roles of glial innate immunity in age-related neurodegeneration, G828200374, Risk Factors, Pathology, and Clinical Expressions of AD, G860030259, Identification and characterization of AD risk networks using multi-dimensional "omics" data, G983864884
OpenAlex ID: W2795614235