CHF5074, a novel gamma-secretase modulator, attenuates brain beta-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease

Br J Pharmacol. 2009 Mar;156(6):982-93. doi: 10.1111/j.1476-5381.2008.00097.x.

Abstract

Background and purpose: We evaluated the effects of 1-(3',4'-dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new gamma-secretase modulator, on brain beta-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP).

Experimental approach: Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet.

Key results: Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not beta-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls.

Conclusions and implications: Chronic CHF5074 treatment reduced brain beta-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel gamma-secretase modulator is a promising therapeutic agent for Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Behavior, Animal / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / pathology
  • Cyclopropanes / pharmacology*
  • Cyclopropanes / therapeutic use
  • Flurbiprofen / analogs & derivatives*
  • Flurbiprofen / pharmacology
  • Flurbiprofen / therapeutic use
  • Humans
  • Ibuprofen / pharmacology
  • Ibuprofen / therapeutic use
  • Learning Disabilities / drug therapy*
  • Memory / drug effects
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / pathology
  • Mutation
  • Peptide Fragments / metabolism
  • Plaque, Amyloid / drug effects*
  • Plaque, Amyloid / pathology

Substances

  • 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclopropanes
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Flurbiprofen
  • Amyloid Precursor Protein Secretases
  • Ibuprofen