Molecular and Pathological Interactions among Aß42, Tau, TREM2, and TYROBP in Drosophila Models

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. In this study, we systematically examined molecular and pathological interactions among Aß, 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. Overall design: We generated RNA-seq expression profiles for flies with "wild type", "glial expression of TREM2/TYROBP", "glial expression of TREM2/TYROBP and neuronal expression of Aß" and "glial expression of TREM2/TYROBP and retinal expression of Tau".