The Streptomyces metabolite anhydroexfoliamycin ameliorates hallmarks of Alzheimer's disease in vitro and in vivo

Neuroscience. 2015 Oct 1:305:26-35. doi: 10.1016/j.neuroscience.2015.07.082. Epub 2015 Aug 3.

Abstract

Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (Aβ) levels, β-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3β) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3β, reducing tau phosphorylation in vitro (0.1 μM). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases.

Keywords: 3xTg-AD; Alzheimer disease; anhydroexfoliamycin; glycogen synthase kinase-3beta; streptomyces; β-secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Anthracenes / therapeutic use*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / therapeutic use*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Aspartic Acid Endopeptidases / metabolism
  • Brain / drug effects
  • Brain / metabolism*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Neuroblastoma / pathology
  • Peptide Fragments / metabolism
  • Presenilin-1 / genetics
  • Prodigiosin / analogs & derivatives*
  • Prodigiosin / chemistry
  • Prodigiosin / therapeutic use
  • tau Proteins / genetics

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Anthracenes
  • Antipsychotic Agents
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • tau Proteins
  • pyrazolanthrone
  • undecylprodigiosin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • MAP Kinase Kinase Kinases
  • Glycogen Synthase Kinase 3
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Prodigiosin