Levistolide A Attenuates Alzheimer's Pathology Through Activation of the PPARγ Pathway

Alzheimer's disease (AD) is a neurodegenerative disease characterized by beta-amyloid (A beta) protein deposition, neurofibrillary tangle (NFT) formation, and neuronal loss in the brain. The current study was designed to investigate the potential mechanisms by which levistolide A affects the pathogenesis of AD in an amyloid precursor protein/presenilin 1 (APP/PS1) transgenic (Tg) mouse model of AD and N2a/APP695swe cells. Specifically, behavioral changes in levistolide A-treated APP/PS1 Tg mice were assessed by the nest-building and Morris water maze (MWM) tests. Levistolide A treatment clearly ameliorated memory deficits and cognitive decline in APP/PS1 Tg mice. A beta generation and the inflammatory response in APP/PS1 Tg mouse brains were clearly reduced after long-term levistolide A application. Mechanistically, levistolide A concurrently stimulated the expression of alpha-secretase and decreased the generation of beta- and gamma-secretases. In addition, levistolide A inhibited the phosphorylation of tau in the brains of the Tg mice. Furthermore,in vitroandin vivoexperiments suggested that peroxisome proliferator-activated receptor gamma (PPAR gamma) is the key transcription factor that mediates the regulatory effects of levistolide A on the expression of alpha-, beta-, and gamma-secretases and phosphorylation of tau. Collectively, these findings show that levistolide A may be a candidate for the treatment of AD.

Automated summary

Livistolide A treatment improved memory deficits and cognitive decline in APP/PS1 Tg mice by stimulating the expression of alpha-secretase and reducing the generation of beta- and gamma-secretases. Inhibition of tau phosphorylation in the brains of Tg mice was also observed. The findings suggest that Livistolide A may be a candidate for AD treatment.