Abstract
BackgroundCerebral 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.MethodsIn 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.ResultsGlial 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.ConclusionsThe 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.
Highlights
Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood
We employed an integrative multiscale network analysis approach to identify key molecular interactions of cellular pathways and causal regulators underlying pathological changes in AD. This approach identified TYROBP, the intracellular adaptor of TREM2, as a key driver of immune- and microgliaspecific networks that are associated with LOAD pathology [11, 13]
While the expression of TYROBP proteins was readily detectable by western blotting, TREM2 protein levels were undetectable, raising the possibility that ectopically expressed human TREM2 proteins may be unstable in fly glial cells perhaps because a binding partner that is required to stabilize TREM2 protein was absent (Fig. 2b)
Summary
Neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. At the level of neuropathology, AD is characterized by aggregation and accumulation of two proteins, β-amyloid peptides (Aβ) and the microtubuleassociated protein tau [1]. Some older individuals with neuropathological AD were asymptomatic during their lifetime [9] These clinicopathological studies indicate that disease progression is a complex process resulting from the interplay of a number of genetic and Sekiya et al Genome Medicine (2018) 10:26 environmental factors, some of which modulate accumulation of neuropathology while others modulate synaptic and neuronal resilience [10]. Along with genomic and clinical information from multiple studies, continue to accumulate and data interpretation is becoming a difficult challenge in these “omics” approaches
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