Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.

Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a centra...

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Autores principales:	Jenifer C Kaldun, Shahnaz R Lone, Ana M Humbert Camps, Cornelia Fritsch, Yves F Widmer, Jens V Stein, Seth M Tomchik, Simon G Sprecher
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/58cca99fbadd4f4a824ce76c47662ce6
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spelling	oai:doaj.org-article:58cca99fbadd4f4a824ce76c47662ce62021-11-25T05:32:53ZDopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.1544-91731545-788510.1371/journal.pbio.3001412https://doaj.org/article/58cca99fbadd4f4a824ce76c47662ce62021-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.3001412https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Pan-neuronal expression of Aβ42Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the Aβ42Arctic-mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic Aβ peptides.Jenifer C KaldunShahnaz R LoneAna M Humbert CampsCornelia FritschYves F WidmerJens V SteinSeth M TomchikSimon G SprecherPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 10, p e3001412 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jenifer C Kaldun Shahnaz R Lone Ana M Humbert Camps Cornelia Fritsch Yves F Widmer Jens V Stein Seth M Tomchik Simon G Sprecher Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
description	Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Pan-neuronal expression of Aβ42Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the Aβ42Arctic-mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic Aβ peptides.
format	article
author	Jenifer C Kaldun Shahnaz R Lone Ana M Humbert Camps Cornelia Fritsch Yves F Widmer Jens V Stein Seth M Tomchik Simon G Sprecher
author_facet	Jenifer C Kaldun Shahnaz R Lone Ana M Humbert Camps Cornelia Fritsch Yves F Widmer Jens V Stein Seth M Tomchik Simon G Sprecher
author_sort	Jenifer C Kaldun
title	Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
title_short	Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
title_full	Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
title_fullStr	Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
title_full_unstemmed	Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
title_sort	dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in drosophila.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/58cca99fbadd4f4a824ce76c47662ce6
work_keys_str_mv	AT jeniferckaldun dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT shahnazrlone dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT anamhumbertcamps dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT corneliafritsch dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT yvesfwidmer dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT jensvstein dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT sethmtomchik dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila AT simongsprecher dopaminesleepandneuronalexcitabilitymodulateamyloidbmediatedforgettingindrosophila
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Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.

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