γ -Secretase Pharmacology: What Pharmacology Will Work for Alzheimer's Disease?

Abstract

This special issue focuses on γ-secretase modulators (GSMs) and inhibitors (GSIs), two classes of small molecules with the potential to test the amyloid hypothesis of Alzheimer's disease. Recent clinical trials of GSI and GSM, including semagacestat, avagacestat, and R-flurbiprofen, have been discontinued for lack of efficacy and/or side effects, the mechanisms of which have not been elucidated. Detrimental effects of GSIs on cognition observed in AD patients may be linked to the accumulation of C-terminal fragment of APP (C99 or CTFβ). The stimulating effects of GSIs on skin cancer in AD patients have been linked to their inhibition of Notch processing. The lack of efficacy of the GSM R-flurbiprofen in AD patients has been explained with its low potency and poor ability to cross the blood-brain barrier. The two review articles and three research articles address key issues for GSI and GSM, namely, Notch-related side effects and drug-like properties, respectively. Although other amyloid-related approaches are continuing in clinical trials, including anti-Aβ antibodies and β-site amyloid precursor protein cleaving enzyme (BACE) inhibitors, it still remains to be seen whether or not they can decrease amyloid or Aβ for a sufficient period of time at tolerable doses in patients. Therefore, renewed efforts toward GSIs and GSMs appear justified.