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

Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila models.
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Sekiya M, Wang M, Fujisaki N, Sakakibara Y, Quan X, Ehrlich ME, De Jager PL, Bennett DA, Schadt EE, Gandy S, Ando K, Zhang B, Iijima KM,


Sekiya M, Wang M, Fujisaki N, Sakakibara Y, Quan X, Ehrlich ME, De Jager PL, Bennett DA, Schadt EE, Gandy S, Ando K, Zhang B, Iijima KM, (click to view)

Sekiya M, Wang M, Fujisaki N, Sakakibara Y, Quan X, Ehrlich ME, De Jager PL, Bennett DA, Schadt EE, Gandy S, Ando K, Zhang B, Iijima KM,

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Genome medicine 2018 03 2910(1) 26 doi 10.1186/s13073-018-0530-9

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.

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