Alzheimer's disease and Notch signaling.
Cleavage of the amyloid precursor protein (APP) by gamma-secretase generates a neurotoxic amyloid beta-peptide (Abeta) that is thought to be associated with the neurodegeneration observed in Alzheimer's disease (AD) patients. Presenilin is the catalytic member of the gamma-secretase proteolytic complex and mutations in presenilins are the major cause of early-onset familial Alzheimer's disease. In addition to APP, gamma-secretase substrates include Notch1 homologues, Notch ligands Delta and Jagged, and additional type I membrane proteins, raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting gamma-secretase. Notch signaling is involved in tumorigenesis as well as in determining the fates of neural and nonneural cells during development and in adults. Alterations in proteolysis of the Notch by gamma-secretase could be involved in the pathogenesis of AD. Inconsistently, several recent observations have indicated that enhanced Notch signaling and expression could be instrumental in neurodegeneration in AD. Therefore, detailed and precise study of Notch signaling in AD is important for elucidating diverse mechanisms of pathogenesis and potentially for treating and preventing Alzheimer's disease.
College of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
Ha-Na
HN
Woo
Jong-Sung
JS
Park
A-Ryeong
AR
Gwon
Thiruma V
TV
Arumugam
Dong-Gyu
DG
Jo
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D006801:Humans; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases