Activity-dependent release of phosphorylated human tau from Drosophila neurons in primary culture.

Autor:	Ismael S; Neuroscience Program, Department of Biological Sciences, and Molecular and Cellular Biology Interdisciplinary Graduate Program, Ohio University, Athens, Ohio, USA., Sindi G; Neuroscience Program, Department of Biological Sciences, and Molecular and Cellular Biology Interdisciplinary Graduate Program, Ohio University, Athens, Ohio, USA., Colvin RA; Neuroscience Program, Department of Biological Sciences, and Molecular and Cellular Biology Interdisciplinary Graduate Program, Ohio University, Athens, Ohio, USA., Lee D; Neuroscience Program, Department of Biological Sciences, and Molecular and Cellular Biology Interdisciplinary Graduate Program, Ohio University, Athens, Ohio, USA. Electronic address: leed1@ohio.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Oct; Vol. 297 (4), pp. 101108. Date of Electronic Publication: 2021 Aug 30.
DOI:	10.1016/j.jbc.2021.101108
Abstrakt:	Neuronal activity can enhance tau release and thus accelerate tauopathies. This activity-dependent tau release can be used to study the progression of tau pathology in Alzheimer's disease (AD), as hyperphosphorylated tau is implicated in AD pathogenesis and related tauopathies. However, our understanding of the mechanisms that regulate activity-dependent tau release from neurons and the role that tau phosphorylation plays in modulating activity-dependent tau release is still rudimentary. In this study, Drosophila neurons in primary culture expressing human tau (hTau) were used to study activity-dependent tau release. We found that hTau release was markedly increased by 50 mM KCl treatment for 1 h. A similar level of release was observed using optogenetic techniques, where genetically targeted neurons were stimulated for 30 min using blue light (470 nm). Our results showed that activity-dependent release of phosphoresistant hTau S11A was reduced when compared with wildtype hTau. In contrast, release of phosphomimetic hTau E14 was increased upon activation. We found that released hTau was phosphorylated in its proline-rich and C-terminal domains using phosphorylation site-specific tau antibodies (e.g., AT8). Fold changes in detectable levels of total or phosphorylated hTau in cell lysates or following immunopurification from conditioned media were consistent with preferential release of phosphorylated hTau after light stimulation. This study establishes an excellent model to investigate the mechanism of activity-dependent hTau release and to better understand the role of phosphorylated tau release in the pathogenesis of AD since it relates to alterations in the early stage of neurodegeneration associated with increased neuronal activity. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu