The structure and function of Alzheimer's gamma secretase enzyme complex.
The production and accumulation of the beta amyloid protein (Abeta) is a key event in the cascade of oxidative and inflammatory processes that characterizes Alzheimer's disease (AD). A multi-subunit enzyme complex, referred to as gamma (gamma) secretase, plays a pivotal role in the generation of Abeta from its parent molecule, the amyloid precursor protein (APP). Four core components (presenilin, nicastrin, aph-1, and pen-2) interact in a high-molecular-weight complex to perform intramembrane proteolysis on a number of membrane-bound proteins, including APP and Notch. Inhibitors and modulators of this enzyme have been assessed for their therapeutic benefit in AD. However, although these agents reduce Abeta levels, the majority have been shown to have severe side effects in pre-clinical animal studies, most likely due to the enzymes role in processing other proteins involved in normal cellular function. Current research is directed at understanding this enzyme and, in particular, at elucidating the roles that each of the core proteins plays in its function. In addition, a number of interacting proteins that are not components of gamma-secretase also appear to play important roles in modulating enzyme activity. This review will discuss the structural and functional complexity of the gamma-secretase enzyme and the effects of inhibiting its activity.
Krishnaswamy
Sudarsan
S
Centre of Excellence for Alzheimer's Disease Research and Care, Edith Cowan University, Joondalup, WA, Australia.
Verdile
Giuseppe
G
Groth
David
D
Kanyenda
Limbikani
L
Martins
Ralph N
RN
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases