FAD-linked mutations in presenilin 1 alter the length of Aβ peptides derived from βAPP transmembrane domain mutants

M. Paul Murphy, Sacha N. Uljon, Todd E. Golde, Rong Wang

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


γ-Secretase is an enzymatic activity responsible for the final cleavage of the amyloid precursor protein leading to the production of the amyloid β-peptide (Aβ). γ-Secretase is likely an aspartyl protease, since its activity can be inhibited by both pepstatin and active-site directed aspartyl protease inhibitors. Recent work has indicated that presenilins 1 and 2 may actually be the γ-secretase enzymes. Presenilin (PS) mutations, which lead to an increase in the production of a longer form of Aβ, are also the most common cause of familial Alzheimer's disease (FAD). Therefore, in an attempt to better characterize the substrate preferences of γ-secretase, we performed experiments to determine how FAD-linked mutations in PS1 would affect the generation of Aβ peptides from full length precursor substrates that we have previously demonstrated to be proteolytically cleaved at alternative sites and/or by enzymatic activities that are pharmacologically distinct. Presenilin mutations increased the production of Aβ peptides from sites distal to the primary cleavage site ('longer' peptides) and in several cases also decreased production of 'shorter' peptides. These results support a model in which the FAD-linked mutants subtly alter the conformation of the γ-secretase complex to favor the production of long Aβ.

Original languageEnglish
Pages (from-to)199-209
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number2
StatePublished - Mar 16 2002

Bibliographical note

Funding Information:
The authors would like to thank K.A. Findlay, H.A. Lookingbill and T.E. Smith for technical assistance. This work was supported by NIA grants AG16065, AG10491 (R.W.), a Beeson Award from the American Federation for Aging Research, an Ellison Medical Foundation New Scholars award, and NIH grant NS39072 (T.E.G.), and John Douglas French Alzheimer’s Foundation and Robert and Clarice Smith Neurodegenerative Disease and Stroke fellowships (to M.P.M.).


  • Alzheimer's disease
  • Amyloid precursor protein
  • Amyloid β-peptide
  • Mass spectrometry
  • Presenilin 1
  • γ-Secretase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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