Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in <italic>Drosophila</italic> models.

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 <italic>TYROBP</italic> 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 <italic>TREM2</italic> and <italic>TYROBP</italic>. Methods: In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic <italic>Drosophila</italic> 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 <italic>TREM2/TYROBP</italic> in driving molecular networks in AD and AD-related phenotypes in flies. [ABSTRACT FROM AUTHOR]