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

Jenifer C Kaldun; Shahnaz R Lone; Ana M Humbert Camps; Cornelia Fritsch; Yves F Widmer; Jens V Stein; Seth M Tomchik; Simon G Sprecher

doi:10.1371/journal.pbio.3001412

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

Journal article

Open access

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

Jenifer C Kaldun, Shahnaz R Lone, Ana M Humbert Camps, Cornelia Fritsch, Yves F Widmer, Jens V Stein, Seth M Tomchik and Simon G Sprecher

PLoS biology, Vol.19(10), pp.e3001412-e3001412

10/2021

DOI: 10.1371/journal.pbio.3001412

PMCID: PMC8523056

PMID: 34613972

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Abstract

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.

Amyloid beta-Peptides - toxicity

Animals

Brain - metabolism

Dopamine - metabolism

Drosophila melanogaster - drug effects

Drosophila melanogaster - physiology

Memory - drug effects

Memory - physiology

Mushroom Bodies - drug effects

Mushroom Bodies - metabolism

Neurons - drug effects

Neurons - physiology

Sleep - physiology

Details

Title: Subtitle: Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila
Creators: Jenifer C Kaldun - University of Fribourg
Shahnaz R Lone - Central University of Punjab
Ana M Humbert Camps - Department of Biology, University of Fribourg, Fribourg, Switzerland
Cornelia Fritsch - University of Fribourg
Yves F Widmer - University of Fribourg
Jens V Stein - University of Fribourg
Seth M Tomchik - Scripps Research Institute
Simon G Sprecher - University of Fribourg
Resource Type: Journal article
Publication Details: PLoS biology, Vol.19(10), pp.e3001412-e3001412
DOI: 10.1371/journal.pbio.3001412
PMID: 34613972
PMCID: PMC8523056
NLM abbreviation: PLoS Biol
ISSN: 1544-9173
eISSN: 1545-7885
Grant note: DOI: 10.13039/501100004784, name: Novartis Stiftung für Medizinisch-Biologische Forschung, award: 18A017; DOI: 10.13039/501100001711, name: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, award: 310030_188471; DOI: 10.13039/501100001711, name: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, award: CRSII5_180316; DOI: 10.13039/501100008947, name: Stiftung Synapsis - Alzheimer Forschung Schweiz AFS
Language: English
Date published: 10/2021
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984303855502771

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