| Autor: |
Kaldun, Jenifer C., Lone, Shahnaz R., Humbert Camps, Ana M., Fritsch, Cornelia, Widmer, Yves F., Stein, Jens V., Tomchik, Seth M., Sprecher, Simon G. |
| Předmět: |
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| Zdroj: |
PLoS Biology; 10/6/2021, Vol. 19 Issue 10, p1-25, 25p, 4 Graphs |
| Abstrakt: |
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. One of the early hallmarks in Alzheimer's disease is increased forgetting. This study shows that restricted expression of amyloid beta in the memory center of fruit flies causes enhanced forgetting without affecting the ability to learn; forgetting is caused by increased excitability and can be restored with drugs, increased sleep or modulation of dopamine signalling. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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