Neuroprotective Effects of Limonene (+) against A beta 42-Induced Neurotoxicity in a Drosophila Model of Alzheimer's Disease

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, p-cymene, limonene (+), limonene (-), linalool, alpha-pinene (+), and beta-pinene (-), partially suppressed the beta amyloid 42 (A beta 42)-induced rough eye phenotype when fed to A beta 42-expressing flies. Among them, limonene (+) restored the decreased survival of flies expressing A beta 42 in neurons during development. Limonene (+) treatment did not affect A beta 42 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 A beta 42-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 A beta 42 and, thus, is a possible therapeutic reagent for AD.