1. Academic Validation
  2. Levistolide A Attenuates Alzheimer's Pathology Through Activation of the PPARγ Pathway

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

  • Neurotherapeutics. 2021 Jan;18(1):326-339. doi: 10.1007/s13311-020-00943-1.
Xiaodan Qu 1 Peipei Guan 1 Li Han 2 Zhanyou Wang 3 Xueshi Huang 1
Affiliations

Affiliations

  • 1 Institute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, People's Republic of China.
  • 2 Institute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang, 110819, People's Republic of China. hanli@mail.neu.edu.cn.
  • 3 Institute of Health Sciences, China Medical University, Shenyang, 110122, People's Republic of China. wangzy@cmu.edu.cn.
Abstract

Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid (Aβ) 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. Aβ 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 α-secretase and decreased the generation of β- and γ-secretases. In addition, levistolide A inhibited the phosphorylation of tau in the brains of the Tg mice. Furthermore, in vitro and in vivo experiments suggested that Peroxisome Proliferator-activated Receptor γ (PPARγ) is the key transcription factor that mediates the regulatory effects of levistolide A on the expression of α-, β-, and γ-secretases and phosphorylation of tau. Collectively, these findings show that levistolide A may be a candidate for the treatment of AD.

Keywords

Alzheimer’s disease; GSK-3β; PPARγ; levistolide A; tau phosphorylation; β-amyloid protein.

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