Cleavage of transmembrane receptors by γ-secretase is the final step in the process of regulated intramembrane proteolysis (RIP) and has a significant impact on receptor function. Although relatively little is known about the molecular mechanism of γ-secretase enzymatic activity, it is becoming clear that substrate dimerization and/or the α-helical structure of the substrate can regulate the si...

Alzheimer’s disease is characterized by protein deposits of amyloid-β as plaques in the brain (1). The suite of enzymes that produce amyloid-β by cutting it out of the amyloid-β precursor protein (APP) have long been considered to be prime targets for therapeutic intervention. Converting this promise into reality, however, continues to be stalled by a series of obstacles, including an inaccurat...

Inhibition of -secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic -amyloid (A ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other -secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by -secretase inhibitors c...

Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have ...

Gamma-secretase is a multisubunit complex with intramembrane proteolytic activity. In humans it was identified in genetic screens of patients suffering from familial forms of Alzheimer's disease, and since then it was shown to mediate cleavage of more than 80 substrates, including amyloid precursor protein or Notch receptor. Moreover, in animals, γ-secretase was shown to be involved in regulati...

γ-secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP) and determines the generation of Aβ which is associated with Alzheimer's disease (AD). Here we identified that an anti-Parkinson's disease drug, Istradefylline, could enhance Aβ generation in various cell lines and primary neuronal cells of APP/PS1 mouse. Moreover, the increased generation of Aβ42 was detect...

γ-Secretase is an intramembrane-cleaving protease that is responsible for the generation of amyloid-β peptides linked to the pathogenesis of Alzheimer's disease. Using a substituted cysteine accessibility method, we have previously shown that the hydrophilic "catalytic pore" structure of γ-secretase is formed by the transmembrane domains (TMDs) 6, 7, and 9 of presenilin 1 (PS1), the catalytic s...

Amyloid beta-peptide (Abeta) is generated by the consecutive cleavages of beta- and gamma-secretase. The intramembraneous gamma-secretase cleavage critically depends on the activity of presenilins (PS1 and PS2). Although there is evidence that PSs are aspartyl proteases with gamma-secretase activity, it remains controversial whether their subcellular localization overlaps with the cellular site...

The presenilin/gamma-secretase complex, an unusual intramembrane aspartyl protease, plays an essential role in cellular signaling and membrane protein turnover. Its ability to liberate numerous intracellular signaling proteins from the membrane and also mediate the secretion of amyloid-beta protein (Abeta) has made modulation of gamma-secretase activity a therapeutic goal for cancer and Alzheim...

Altered production of β-amyloid (Aβ) from the amyloid precursor protein (APP) is closely associated with Alzheimer's disease (AD). APP has a number of homo- and hetero-dimerizing domains, and studies have suggested that dimerization of β-secretase derived APP carboxyl terminal fragment (CTFβ, C99) impairs processive cleavage by γ-secretase increasing production of long Aβs (e.g., Aβ1-42, 43). O...