Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1

EBioMedicine. 2017 Oct;24:93-101. doi: 10.1016/j.ebiom.2017.08.028. Epub 2017 Sep 4.

Abstract

A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.

Keywords: Alzheimer's disease; Notch; β-amyloid; β-amyloid precursor protein; γ-secretase; γ-secretase modulator.

MeSH terms

  • Allosteric Site
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Disease Models, Animal
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Mice
  • Mice, Transgenic
  • Neurons / cytology*
  • Neurons / metabolism
  • Presenilin-1 / chemistry*
  • Presenilin-1 / metabolism
  • Protein Conformation / drug effects

Substances

  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • PSEN1 protein, human
  • Presenilin-1
  • Amyloid Precursor Protein Secretases