Novel Mechanism of γ-Secretase Modulation


It is widely believed that reducing amyloid plaque formation will provide a disease-modifying treatment for Alzheimer’s Disease, either halting or slowing cognitive decline. Amyloid peptides, which aggregate to form neurotoxic plaques, are formed by proteolysis of a precursor protein by the action of two enzymes, β-secretase and γ-secretase. Inhibition of either of these proteases should prevent the formation of amyloid peptides, and much effort has been devoted to the identification of inhibitors. γ-Secretase, particularly, is a promiscuous enzyme and hydrolyses a number of other substrates, including Notch. The Notch signalling pathway is important in many cellular processes and so modulators rather than inhibitors of γ-secretase are preferred.

Amyloid pathway

Relatively early in the search for modulators of γ-secretase, the surprising discovery was made that certain nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, effectively suppress amyloid peptide production while sparing processing of Notch and other γ-secretase substrates. Further studies identified tarenflurbil (R-flurbiprofen, Flurizan, MPC-7869) as a γ-secretase modulator with the potential to treat Alzheimer’s Disease. A recent report in Nature (Kukar et. al., Nature 2008, 453, 925-929) has now shed new light on how such compounds prevent amyloid formation.


Using photoprobes, the group were able to show that flurbiprofen does not bind to the γ-secretase protein complex but, instead, binds to the amyloid precursor protein.

Disappointingly, Myriad Genetics have recently discontinued development of Flurizan since it failed in a phase III clinical trial in Alzheimer’s patients.

The study by Kukar et. al. does, however, suggest that it may be possible to identify other small molecules that reduce the formation of amyloid peptides by binding to the precursor protein rather than to the γ-secretase complex. It remains to be seen whether similar ‘substrate-binding’ inhibitors of other proteases can be identified.

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