Researchers from France reported success in synthesizing novel compounds that specifically target γ-secretase cleavage of amyloid-β (Aβ) peptide, without affecting the enzyme's cleavage of other substrates such as Notch and possibly Ire1. Fréderic Checler from the Institut de Pharmacologie Moleculaire et Cellulaire in Nice, France, and Jean-Louis Kraus from Trophos, Inc., Marseille, France, describe their findings in the May issue of Nature Cell Biology (

γ-secretase has been a hotly pursued drug target because of its role in snipping the amyloid precursor protein and releasing the Aβ fragment, which accumulates in the brains of Alzheimer's patients and is thought by many scientists to cause the disease. There have been concerns, however, that blocking γ-secretase would also affect the metabolism of other proteins, particularly Notch, and result in unwanted side effects. The new compounds promise a clean hit at Aβ. It remains to be seen whether these drugs would be toxic to animals or humans, and also whether they would in fact cure Alzheimer's disease.—Hakon Heimer


  1. It is an unexpected finding of the occurrence of an inhibitor to block APP-gamma secretase but not Notch processing. Although we do not know the physiological function of the soluble secreted amyloid protein, it is now potent to exclusively regulate APP metabolism.

    View all comments by Hiroshi Mori

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Primary Papers

  1. . New protease inhibitors prevent gamma-secretase-mediated production of Abeta40/42 without affecting Notch cleavage. Nat Cell Biol. 2001 May;3(5):507-11. PubMed.