title: Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?
abstract: BACKGROUND
  Compounds that inhibit or modulate γ-secretase, the pivotal enzyme which generates β-amyloid (Aβ), are potential therapeutics for Alzheimer's disease (AD).
  
  
  METHODS
  This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic and discusses the clinical issues surrounding this new class of anti-AD compounds.
  
  
  CONCLUSIONS
  γ-Secretase inhibitors may cause significant toxicity in humans. Two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of detrimental cognitive and functional effects of the drug. These detrimental effects were mainly ascribed to the inhibition of Notch processing and the accumulation of the neurotoxic precursor of Aβ resulting from the block of the γ-secretase cleavage activity on amyloid precursor protein. New Notch-sparing γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks. It has also been argued that γ-secretase inhibitors should be used in the very early stages of the disease progression when neuronal loss is still limited. Thus, the inclusion of patients with mild-to-moderate AD in the semagacestat Phase III trials could also explain the negative outcome of these studies. Understanding the reasons for this failure may be important for future research on effective treatments for this devastating disease.
authors.affiliation: Research & Development Department, Chiesi Farmaceutici, Via Palermo 26/A, Parma, Italy. b.imbimbo@chiesigroup.com
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
authors.forename: Francesco
authors.initials: F
authors.lastname: Panza
authors.forename: Vincenza
authors.initials: V
authors.lastname: Frisardi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Solfrizzi
authors.forename: Grazia
authors.initials: G
authors.lastname: D'Onofrio
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Logroscino
authors.forename: Davide
authors.initials: D
authors.lastname: Seripa
authors.forename: Alberto
authors.initials: A
authors.lastname: Pilotto
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases