Drosophila appear resistant to trans-synaptic tau propagation.

Autor:	Catterson JH; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.; UK Dementia Research Institute, The University of Edinburgh, Edinburgh EH8 9XD, UK., Mouofo EN; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.; UK Dementia Research Institute, The University of Edinburgh, Edinburgh EH8 9XD, UK., López De Toledo Soler I; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK., Lean G; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK., Dlamini S; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK., Liddell P; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK., Voong G; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK., Katsinelos T; Schaller Research Group at the University of Heidelberg and the DKFZ, German Cancer Research Center, Proteostasis in Neurodegenerative Disease (B180), INF 581, 69120 Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, INF 234, 69120 Heidelberg, Germany., Wang YC; VIB-KU Leuven Center for Brain & Disease Research, Department of Neurosciences, 3000 Leuven, Belgium.; KU Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium., Schoovaerts N; VIB-KU Leuven Center for Brain & Disease Research, Department of Neurosciences, 3000 Leuven, Belgium.; KU Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium., Verstreken P; VIB-KU Leuven Center for Brain & Disease Research, Department of Neurosciences, 3000 Leuven, Belgium.; KU Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium., Spires-Jones TL; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.; UK Dementia Research Institute, The University of Edinburgh, Edinburgh EH8 9XD, UK., Durrant CS; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.; UK Dementia Research Institute, The University of Edinburgh, Edinburgh EH8 9XD, UK.
Jazyk:	angličtina
Zdroj:	Brain communications [Brain Commun] 2024 Aug 08; Vol. 6 (4), pp. fcae256. Date of Electronic Publication: 2024 Aug 08 (Print Publication: 2024).
DOI:	10.1093/braincomms/fcae256
Abstrakt:	Alzheimer's disease is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of Alzheimer's disease is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models, and indirect evidence for tau spread via synapses has been observed in human Alzheimer's disease. Halting tau propagation is a promising therapeutic target for Alzheimer's disease; thus, a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau in Drosophila melanogaster . Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing four different human tau constructs in two distinct neuronal populations reveals a robust resistance in Drosophila to the trans-synaptic spread of human tau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global human tau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that Drosophila expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in Drosophila may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies. Competing Interests: T.L.S.-J. is the founding editor of Brain Communications. She had no involvement in the review process of this submission. T.L.S.-J. is on the scientific advisory boards of Cognition Therapeutics and Scottish Brain Sciences. P.V. is the scientific founder of Jay Therapeutics. None had any involvement in the current work. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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