The -secretase complex catalyzes the final intramembraneous cleavage of the -amyloid precursor protein, liberating the neurotoxic amyloid -peptide implicated in Alzheimer’s disease. Apart from the catalytic subunit presenilin (PS), three additional subunits, nicastrin, APH-1, and PEN-2, have been identified. In mammals, two PS homologues, PS1 and PS2, which are part of distinct -secretase compl...

The Notch pathway is dysregulated and a potential target in glioblastoma multiforme (GBM). Currently available Notch inhibitors block γ-secretase, which is necessary for Notch processing. However, Notch is first cleaved by α-secretase outside the plasma membrane, via a disintegrin and metalloproteinase-10 and -17. In this work, we used a potent α-secretase inhibitor (ASI) to test inhibition of ...

The study was undertaken to explore whether piperlonguminine/dihydropiperlonguminine could inhibit the production of amyloidbeta (Abeta) in human neuroblastoma cells (SK-N-SH) and to examine the underlying mechanism of this effect. Piperlonguminine/dihydropiperlonguminine components (1:0.8) were extracted from Futokadsura stem, and then used to treat SK-N-SH cells at three different concentrati...

Presenilins are considered to be the catalytic subunits of the gamma-secretase complex and are therefore drug targets for Alzheimer's disease. They are also essential for the fine tuning of the immunological system and for memory and synaptic plasticity. Genetic ablation in the forebrain results in a progressive neurodegenerative process that is independent from Abeta generation. The question a...

The structure and function of the gamma-secretase proteases are of great interest because of their crucial roles in cellular and disease processes. We established a novel purification protocol for the gamma-secretase complex that involves a conformation- and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the gamma-secret...

Presenilin (PS-1) is part of the protease gamma-secretase that cleaves the membrane proteins APP and Notch. In this issue of Cell, Marambaud et al. report that PS-1 cleaves the cell adhesion molecule N-cadherin, releasing a C-terminal fragment that promotes degradation of the transcriptional coactivator CBP. Mutations in PS-1 associated with Alzheimer's disease interfere with CBP proteolysis, l...

Some forms of familial Alzheimer's disease (FAD) are caused by mutations in presenilins (PSs), catalytic components of a γ-secretase complex that cleaves target proteins, including amyloid precursor protein (APP). Calcium (Ca(2+)) dysregulation in cells with these FAD-causing PS mutants has been attributed to attenuated store-operated Ca(2+) entry [SOCE; also called capacitative Ca(2+) entry (C...

The gamma-secretase complex is required for intramembrane cleavage of several integral membrane proteins, including the Notch receptor, where it generates an active signaling fragment. Four putative gamma-secretase components have been identified-presenilin (Psn), nicastrin (Nct), Aph-1, and Pen-2. Here, we use a stepwise coexpression approach to investigate the role of each new component in ga...

Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated intramembrane proteolysis, in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is unknown whether they can exploit this new signaling mechanism. Here we used a system-w...

-Secretase is the protease responsible for amyloid peptide release and is needed for Notch, N-Cadherin, and possibly other signaling pathways. The protease complex consists of at least four subunits, i.e., Presenilin, Aph1, Pen2, and Nicastrin. Two different genes encode Aph1A and Aph1B in man. A duplication of Aph1B in rodents has given rise to a third gene, Aph1C. Different mixes of -secretas...