Τίτλος:
Amyloid toxicity in a Drosophila Alzheimer's model is ameliorated by autophagy activation
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2021
Συγγραφείς:
Tsakiri, E.N.
Gumeni, S.
Manola, M.S.
Trougakos, I.P.
Περιοδικό:
Neurobiology of Aging
Εκδότης:
ELSEVIER SCIENCE INC 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
Λέξεις-κλειδιά:
amyloid precursor protein; amyloid protein; autophagy related protein 8 family; beta secretase 1; transcription factor Nrf2; amyloid precursor protein; Atg8a protein, Drosophila; bromisoval; Drosophila protein; NFE2L2 protein, human; proteasome; tenebral; transcription factor Nrf2, Alzheimer disease; animal experiment; animal tissue; Article; Atg8a gene; autophagy (cellular); controlled study; disease exacerbation; disease severity; Drosophila; female; gene expression; hAPP gene; hBACE1 gene; heat stress; lifespan; male; mechanical stress; nerve degeneration; nonhuman; Nrf2 gene; phenotype; protein expression; signal transduction; toxicity; ubiquitination; upregulation; Alzheimer disease; animal; autophagy; disease model; Drosophila; drug combination; genetics; metabolism; pathology; physiology, Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Autophagy; Bromisovalum; Disease Models, Animal; Drosophila; Drosophila Proteins; Drug Combinations; Nerve Degeneration; NF-E2-Related Factor 2; Proteasome Endopeptidase Complex
DOI:
10.1016/j.neurobiolaging.2021.04.017
