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

Author:

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

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 42Arctic 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 42Arctic-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 peptides.

Funder

Novartis Stiftung für Medizinisch-Biologische Forschung

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Stiftung Synapsis - Alzheimer Forschung Schweiz AFS

Publisher

Public Library of Science (PLoS)

Subject

General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Neuroscience

Reference117 articles.

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