Amyloid toxicity in a Drosophila Alzheimer's model is ameliorated by autophagy activation

•Expression of hAPP, hBACE1 in flies induces degeneration and stress-sensitivity.•hAPP, hBACE1 expression in flies inhibits proteasome and increases oxidative stress.•Prosβ5 or Nrf2 overexpression does not rescue hAPP, hBACE1 induced neurodegeneration.•Overexpression of Atg8a decelerates hAPP, hBACE...

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Bibliographic Details
Published in:Neurobiology of aging 2021-09, Vol.105, p.137-147
Main Authors: Tsakiri, Eleni N., Gumeni, Sentiljana, Manola, Maria S., Trougakos, Ioannis P.
Format: Article
Language:English
Subjects:
Alzheimer Disease - etiology
Alzheimer Disease - genetics
Alzheimer Disease - pathology
Alzheimer Disease - therapy
Alzheimer's disease
Amyloid beta-Protein Precursor - adverse effects
Amyloid beta-Protein Precursor - metabolism
Animals
APP
autophagy
Autophagy - genetics
Autophagy - physiology
Bromisovalum
Disease Models, Animal
Drosophila
Drosophila Proteins - metabolism
Drosophila Proteins - physiology
Drug Combinations
Nerve Degeneration - genetics
Nerve Degeneration - pathology
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nrf2
proteasome
Proteasome Endopeptidase Complex - metabolism
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Summary:•Expression of hAPP, hBACE1 in flies induces degeneration and stress-sensitivity.•hAPP, hBACE1 expression in flies inhibits proteasome and increases oxidative stress.•Prosβ5 or Nrf2 overexpression does not rescue hAPP, hBACE1 induced neurodegeneration.•Overexpression of Atg8a decelerates hAPP, hBACE1 mediated neurodegeneration.•Atg8a overexpression in hAPP, hBACE1 Tg flies enhanced stress-resistance and lifespan. Alzheimer's disease (AD) is the prevailing form of dementia. Protein degradation and antioxidant pathways have a critical role in preventing the accumulation of protein aggregation; thus, failure of proteostasis in neurons along with redox imbalance mark AD. Herein, we exploited an AD Drosophila model expressing human amyloid precursor (hAPP) and beta-secretase 1 (hBACE1) proteins, to better understand the role of proteostatic or antioxidant pathways in AD. Ubiquitous expression of hAPP, hBACE1 in flies caused more severe degenerative phenotypes versus neuronal targeted expression; it also, suppressed proteasome activity, increased oxidative stress and significantly enhanced stress-sensitivity. Overexpression of Prosβ5 proteasomal subunit or Nrf2 transcription factor in AD Drosophila flies partially restored proteasomal activity but did not rescue hAPP, hBACE1 induced neurodegeneration. On the other hand, expression of autophagy-related Atg8a in AD flies decelerated neurodegeneration, increased stress-resistance, and improved flies' health-/lifespan. Overall, our data suggest that the noxious effects of amyloid-beta aggregates can be alleviated by enhanced autophagy, thus dietary or pharmacological interventions that target autophagy should be considered in AD therapeutic approaches.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2021.04.017