Human Tau aggregates are permissive to protein synthesis-dependent memory in Drosophila tauopathy models
Human Tau aggregates are permissive to protein synthesis-dependent memory in Drosophila tauopathy models
Tauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the
Drosophila tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant. We demonstrate that these neuroplasticity defects are reversible on suppression of new transgenic human Tau expression and surprisingly correlate with an increase in Tau aggregates. Inhibition of aggregate formation via acute oral administration of methylene blue results in re-emergence of deficient memory in animals with suppressed human Tau (hTau)
0N4R expression. Significantly, aggregate inhibition results in PSD-M deficits in hTau
0N3R-expressing animals, which present elevated aggregates and normal memory if untreated with methylene blue. Moreover, methylene blue-dependent hTau
0N4R aggregate suppression within adult mushroom body neurons also resulted in emergence of memory deficits. Therefore, deficient PSD-M on human Tau expression in the
Drosophila CNS is not a consequence of toxicity and neuronal loss because it is reversible. Furthermore, PSD-M deficits do not result from aggregate accumulation, which appears permissive, if not protective of processes underlying this memory variant.
SIGNIFICANCE STATEMENT Intraneuronal Tau aggregate accumulation has been proposed to underlie the cognitive decline and eventual neurotoxicity that characterizes the neurodegenerative dementias known as tauopathies. However, we show in three experimental settings that Tau aggregates in the
Drosophila CNS do not impair but rather appear to facilitate processes underlying protein synthesis-dependent memory within affected neurons.
Drosophila, memory, methylene blue, tau, tau aggregation, tauopathies
2988-3006
Vourkou, Ergina
b3a4e167-7316-45d1-9894-500a82556bcd
Rouiz Ortega, Eva D.
bbaea272-9abf-4186-8c95-a84b140684fb
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Mudher, Amrit
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Skoulakis, Efthimios M.C.
b1aedf6f-214d-4a95-bb12-1901702748f7
19 April 2023
Vourkou, Ergina
b3a4e167-7316-45d1-9894-500a82556bcd
Rouiz Ortega, Eva D.
bbaea272-9abf-4186-8c95-a84b140684fb
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Mudher, Amrit
ce0ccb35-ac49-4b6c-92b4-8dd5e78ac119
Skoulakis, Efthimios M.C.
b1aedf6f-214d-4a95-bb12-1901702748f7
Vourkou, Ergina, Rouiz Ortega, Eva D., Mahajan, Sumeet, Mudher, Amrit and Skoulakis, Efthimios M.C.
(2023)
Human Tau aggregates are permissive to protein synthesis-dependent memory in Drosophila tauopathy models.
The Journal of Neuroscience, 43 (16), .
(doi:10.1523/JNEUROSCI.1374-22.2023).
Abstract
Tauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the
Drosophila tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant. We demonstrate that these neuroplasticity defects are reversible on suppression of new transgenic human Tau expression and surprisingly correlate with an increase in Tau aggregates. Inhibition of aggregate formation via acute oral administration of methylene blue results in re-emergence of deficient memory in animals with suppressed human Tau (hTau)
0N4R expression. Significantly, aggregate inhibition results in PSD-M deficits in hTau
0N3R-expressing animals, which present elevated aggregates and normal memory if untreated with methylene blue. Moreover, methylene blue-dependent hTau
0N4R aggregate suppression within adult mushroom body neurons also resulted in emergence of memory deficits. Therefore, deficient PSD-M on human Tau expression in the
Drosophila CNS is not a consequence of toxicity and neuronal loss because it is reversible. Furthermore, PSD-M deficits do not result from aggregate accumulation, which appears permissive, if not protective of processes underlying this memory variant.
SIGNIFICANCE STATEMENT Intraneuronal Tau aggregate accumulation has been proposed to underlie the cognitive decline and eventual neurotoxicity that characterizes the neurodegenerative dementias known as tauopathies. However, we show in three experimental settings that Tau aggregates in the
Drosophila CNS do not impair but rather appear to facilitate processes underlying protein synthesis-dependent memory within affected neurons.
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e-pub ahead of print date: 19 April 2023
Published date: 19 April 2023
Additional Information:
Funding Information:
This work was supported in part by Phenotypos Grant MIS: 5002135, General Secretariat for Research and Technology Grant 2018ΣE01300001, Greece and the European Union–European Regional Development Fund, and the Flagship Initiative for Neurodegenerative Diseases Research on the Basis of Precision Medicine Project Infrastructures for National Research Networks for Precision Medicine and Climate Change. We thank the Bloomington Drosophila Stock Center for stocks; Dr. Martin Chow, University of Kentucky, for the 0N4R cDNA; Dr. Katerina Papanikolopoulou, Biomedical Sciences Research Centre (BSRC) Alexander Fleming, for help with construction of the double transgenic line; Maro Loizou, BSRC Alexander Fleming, for technical help; and Dr. Iris Nandhakumar, University of Southampton, for help with the Atomic Force Microscopy experiments. The authors declare no competing financial interests. Correspondence should be addressed to Efthimios M.C. Skoulakis at skoulakis@fleming.gr. https://doi.org/10.1523/JNEUROSCI.1374-22.2023 Copyright © 2023 the authors
Funding Information:
This work was supported in part by Phenotypos Grant MIS: 5002135, General Secretariat for Research and Technology Grant 2018RE01300001, Greece and the European Union-European Regional Development Fund, and the Flagship Initiative for Neurodegenerative Diseases Research on the Basis of Precision Medicine Project Infrastructures for National Research Networks for Precision Medicine and Climate Change. We thank the Bloomington Drosophila Stock Center for stocks; Dr. Martin Chow, University of Kentucky, for the 0N4R cDNA; Dr. Katerina Papanikolopoulou, Biomedical Sciences Research Centre (BSRC) Alexander Fleming, for help with construction of the double transgenic line; Maro Loizou, BSRC Alexander Fleming, for technical help; and Dr. Iris Nandhakumar, University of Southampton, for help with the Atomic Force Microscopy experiments. The authors declare no competing financial interests.
Publisher Copyright:
Copyright © 2023 the authors.
Keywords:
Drosophila, memory, methylene blue, tau, tau aggregation, tauopathies
Identifiers
Local EPrints ID: 477335
URI: http://eprints.soton.ac.uk/id/eprint/477335
ISSN: 0270-6474
PURE UUID: 25df4259-e202-44ef-9ea4-9e3f25f0f51b
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Date deposited: 05 Jun 2023 16:34
Last modified: 06 Jun 2024 01:45
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Contributors
Author:
Ergina Vourkou
Author:
Eva D. Rouiz Ortega
Author:
Efthimios M.C. Skoulakis
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