From the multifactorial nature of Alzheimer`s disease to multitarget therapy: the contribution of the translational approach

Curr Top Med Chem. 2013;13(15):1843-52. doi: 10.2174/15680266113139990140.

Abstract

The drug discovery for disease-modifying agents in Alzheimer disease (AD) is facing a failure of clinical trials with drugs based on two driving hypotheses, i.e. the cholinergic and amyloidogenic hypotheses. In this article we recapitulate the main aspects of AD pathology, focusing on possible mechanisms for synaptic dysfunction, neurodegeneration and inflammation. We then present the pharmacological and neurobiological profile of a novel compound (CHF5074) showing both anti-inflammatory and gamma-secretase modulatory activities, discussing the possible time-window for effective treatment in an AD transgenic mouse model. Finally, the concept of cognitive reserve is introduced as possible target for preventive therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / therapeutic use
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / therapeutic use
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / therapeutic use
  • Flurbiprofen / analogs & derivatives*
  • Flurbiprofen / chemical synthesis
  • Flurbiprofen / therapeutic use
  • Humans
  • Inflammation / drug therapy
  • Mice
  • Mice, Transgenic
  • Nootropic Agents / chemical synthesis*
  • Nootropic Agents / therapeutic use
  • Synapses / drug effects
  • Synapses / pathology
  • Synaptic Transmission / drug effects
  • Translational Medical Research

Substances

  • 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid
  • Anti-Inflammatory Agents
  • Cyclopropanes
  • Enzyme Inhibitors
  • Nootropic Agents
  • Flurbiprofen
  • Amyloid Precursor Protein Secretases