Neuroprotective Effects of Limonene (+) against Aβ42-Induced Neurotoxicity in a Drosophila Model of Alzheimer's Disease

Biol Pharm Bull. 2020 Mar 1;43(3):409-417. doi: 10.1248/bpb.b19-00495. Epub 2019 Dec 24.


Forest bathing is suggested to have beneficial effects on various aspects of human health. Terpenes, isoprene based-phytochemicals emitted from trees, are largely responsible for these beneficial effects of forest bathing. Although the therapeutic effects of terpenes on various diseases have been revealed, their effects on neuronal health have not yet been studied in detail. Here, we screened 16 terpenes that are the main components of Korean forests using Drosophila Alzheimer's disease (AD) models to identify which terpenes have neuroprotective effects. Six out of the 16 terpenes, ρ-cymene, limonene (+), limonene (-), linalool, α-pinene (+), and β-pinene (-), partially suppressed the beta amyloid 42 (Aβ42)-induced rough eye phenotype when fed to Aβ42-expressing flies. Among them, limonene (+) restored the decreased survival of flies expressing Aβ42 in neurons during development. Limonene (+) treatment did not affect Aβ42 accumulation and aggregation, but did cause to decrease cell death, reactive oxygen species levels, extracellular signal-regulated kinase phosphorylation, and inflammation in the brains or the eye imaginal discs of Aβ42-expressing flies. This neuroprotective effect of limonene (+) was not associated with autophagic activity. Our results suggest that limonene (+) has a neuroprotective function against the neurotoxicity of Aβ42 and, thus, is a possible therapeutic reagent for AD.

Keywords: Alzheimer’s disease; Drosophila; amyloid β42; limonene (+); terpene.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Animals, Genetically Modified
  • Autophagy / drug effects
  • Brain / metabolism
  • Disease Models, Animal
  • Drosophila melanogaster
  • Limonene / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Neuroglia / drug effects
  • Neuroprotective Agents / pharmacology*
  • Peptide Fragments / toxicity
  • Phosphorylation / drug effects
  • Reactive Oxygen Species / metabolism
  • Survival
  • Terpenes / pharmacology*


  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Peptide Fragments
  • Reactive Oxygen Species
  • Terpenes
  • amyloid beta-protein (1-42)
  • Limonene