Processes of beta-amyloid and intracellular cytoplasmic domain generation by presenilin/gamma-secretase.
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.
Tagami
Shinji
S
Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Osaka, Japan.
Okochi
Masayasu
M
Fukumori
Akio
A
Jiang
Jingwei
J
Yanagida
Kanta
K
Nakayama
Taisuke
T
Morihara
Takashi
T
Tanaka
Toshihisa
T
Kudo
Takashi
T
Takeda
Masatoshi
M
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
D016229:Amyloid beta-Peptides; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases