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bioRxiv · 10.1101/2020.08.18.254649

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice

Audrain, M.·Haure-Mirande, J.-V.·Mleczko, J.·Wang, M.·Griffin, J. K.·Fraser, P.·Zhang, B.·Gandy, S.·Ehrlich, M. E.
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Abstract

Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimers disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgf{beta} and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-{beta} (A{beta}) deposits. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype.

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Audrain, M., Haure-Mirande, J.-V., Mleczko, J., Wang, M., Griffin, J. K., Fraser, P., Zhang, B., Gandy, S., Ehrlich, M. E.. 2020-08-19. Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice. https://doi.org/10.1101/2020.08.18.254649

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