RRC ID 70739
Author Kaldun JC, Lone SR, Humbert Camps AM, Fritsch C, Widmer YF, Stein JV, Tomchik SM, Sprecher SG.
Title Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.
Journal PLoS Biol
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.
Volume 19(10)
Pages e3001412
Published 2021-10-1
DOI 10.1371/journal.pbio.3001412
PMID 34613972
PMC PMC8523056
MeSH 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*
IF 7.076
Drosophila DGRC#106098