33 Scopus citations


Presenilins (PSs) are catalytic components of the γ-secretase proteolytic complexes that produce Aβ and cell signaling peptides γ-Secretase substrates are mostly membrane-bound peptides derived following proteolytic cleavage of the extracellular domain of type I transmembrane proteins. Recent work reveals that γ-secretase substrate processing is regulated by proteins termed γ-secretase substrate recruiting factors (γSSRFs) that bridge substrates to γ-secretase complexes. These factors constitute novel targets for pharmacological control of specific γ-secretase products, such as Aβ and signaling peptides. PS familial Alzheimer's disease (FAD) mutants cause a loss of γ-secretase cleavage function at epsilon sites of substrates thus inhibiting production of cell signaling peptides while promoting accumulation of uncleaved toxic substrates. Importantly, γ-secretase inhibitors may cause toxicity in vivo by similar mechanisms. Here we review novel mechanisms that control γ-secretase substrate selection and cleavage and examine their relevance to AD.

Original languageEnglish
Pages (from-to)166-175
Number of pages10
JournalProgress in Neurobiology
Issue number2
StatePublished - Aug 2012


  • ADAMs
  • Alzheimer's disease
  • FAD mutations cause loss of γ-secretase activity
  • Metalloproteinases
  • Presenilin
  • Toxic substrates
  • γ-Secretase substrate recruiting factors (γSSRFs)
  • γ-Secretase-produced signaling peptides


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