title: Processes of beta-amyloid and intracellular cytoplasmic domain generation by presenilin/gamma-secretase.
abstract: OBJECTIVE
  Following extracellular shedding, transmembrane domains (TMs) of beta-amyloid precursor protein (betaAPP) and Notch-1 undergo proteolysis by presenilin (PS)/gamma-secretase at least at two sites, near the middle of the TM (gamma-/S4 cleavage) and at the interface between cytosol and the TM (epsilon-/S3 cleavage), releasing Alzheimer disease (AD)-associated beta-amyloid (Abeta)/Notch-1beta (Nbeta) and betaAPP intracellular cytoplasmic domain (AICD)/Notch-1 intracellular cytoplasmic domain (NICD). Inhibiting PS/gamma-secretase activity is an essential approach to AD treatment, but it also decreases NICD production, which may cause severe side effects. Therefore, it is important to investigate the differences between the cleavages at the two sites. Gamma-/S4 and epsilon-cleavages have diversity, and produce a number of Abeta/Nbeta and AICD species. S3 cleavage diversity has been recently identified. It is significant that each cleavage occurs with strict precision, not randomly.
  
  
  METHODS
  Biochemical analysis of cultured cells was performed to explore the processing mechanisms.
  
  
  RESULTS
  Familial AD-associated PS1 mutations as well as a subset of nonsteroidal anti-inflammatory drugs cause similar changes in gamma-/S4 cleavage precision, suggesting a common process for these cleavages near the middle of the TM. While the precision of the epsilon-cleavage is drastically affected by physiological factors, that of epsilon-/S3 cleavage is not.
  
  
  CONCLUSIONS
  The processes of the two cleavages occurring in different portions of TMs may be diverse, thus representing possible targets for anti-AD therapeutics to selectively reduce Abeta.
authors.affiliation: Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tagami
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.forename: Akio
authors.initials: A
authors.lastname: Fukumori
authors.forename: Jingwei
authors.initials: J
authors.lastname: Jiang
authors.forename: Kanta
authors.initials: K
authors.lastname: Yanagida
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Morihara
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism / Q000502:physiology; D053763:Presenilins / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases