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

Neurobiol Aging. 2021 Sep;105:137-147. doi: 10.1016/j.neurobiolaging.2021.04.017. Epub 2021 Apr 28.

Abstract

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.

Keywords: APP; Alzheimer's disease; Drosophila; Nrf2; autophagy; proteasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Protein Precursor / adverse effects
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Autophagy / genetics*
  • Autophagy / physiology*
  • Bromisovalum
  • Disease Models, Animal
  • Drosophila Proteins / metabolism
  • Drosophila Proteins / physiology
  • Drosophila*
  • Drug Combinations
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Proteasome Endopeptidase Complex / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • Atg8a protein, Drosophila
  • Drosophila Proteins
  • Drug Combinations
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Bromisovalum
  • tenebral
  • Proteasome Endopeptidase Complex