Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease

EMBO Rep. 2007 Feb;8(2):141-6. doi: 10.1038/sj.embor.7400897.

Abstract

Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the gamma-secretase complex, which affects several downstream signalling pathways. Consequently, the current genetic terminology is misleading. In fact, the available data indicate that several clinical presenilin mutations also lead to a decrease in amyloid precursor protein-derived amyloid beta-peptide generation, further implying that presenilin mutations are indeed loss-of-function mutations. The loss of function of presenilin causes incomplete digestion of the amyloid beta-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease. In this review, I evaluate the implications of this model for the amyloid-cascade hypothesis and for the efficacy of presenilin/gamma-secretase as a drug target.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / genetics*
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases / genetics*
  • Amyloid beta-Peptides / metabolism*
  • Humans
  • Models, Biological*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Peptide Fragments / metabolism*
  • Presenilins / genetics*
  • Presenilins / metabolism*
  • Protein Conformation

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Presenilins
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases