PE859, A Novel Curcumin Derivative, Inhibits Amyloid-β and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8

J Alzheimers Dis. 2017;59(1):313-328. doi: 10.3233/JAD-161017.

Abstract

Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

Keywords: Aggregation inhibitor; Alzheimer’s disease; amyloid-β; tau.

MeSH terms

  • Aging / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / ultrastructure
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / ultrastructure
  • Cell Line, Tumor
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Indoles / therapeutic use*
  • L-Lactate Dehydrogenase / metabolism
  • Maze Learning / drug effects
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Motor Activity / drug effects
  • Neuroblastoma / pathology
  • Protein Aggregates / drug effects*
  • Pyrazoles / therapeutic use*
  • Quartz Crystal Microbalance Techniques
  • Time Factors
  • tau Proteins / metabolism*
  • tau Proteins / ultrastructure

Substances

  • 3-(2-(1H-indol-6-yl)ethenyl)-5-(2-(2-methoxy-4-(2-pyridylmethoxy)phenyl)ethenyl)-1H-pyrazole
  • Amyloid beta-Peptides
  • Indoles
  • Protein Aggregates
  • Pyrazoles
  • tau Proteins
  • L-Lactate Dehydrogenase