40 RESULTS
COMMENT These cognitive effects, along with the adverse events in the gastrointestinal tract and skin, are troubling, as they are similar to the outcomes Lilly had with semagacestat. It's not the end of γ-secretase as a target, but it says that, first and fo
COMMENT This paper describes the detailed structure of a membrane-embedded aspartyl protease called Flak, a preflagellin peptidase (PFP) from an extremophile that has been categorized as a "GXGD aspartyl protease," along with presenilin and SPP. As this
COMMENT This is a solid study that provides important confirmation that presenilin is a zymogen that cuts itself (i.e., it is its own “presenilinase”) and that autoproteolysis occurs stepwise, every ~3 amino acids, similar to what is seen with γ-secretase substra
COMMENT This report provides a very thorough and systematic analysis of the role of the various transmembrane domains of PS1 in γ-secretase assembly, stability and activation. The evidence largely supports the role of specific TM domains in the various steps in t
COMMENT The new report by Page et al. describes important results that address the controversial issue of the mechanism of NSAID-type γ-secretase modulators (GSMs), particularly whether the compounds interact with enzyme or substrate to elicit their effects. Cert
COMMENT This is an intriguing paper describing the surprising discovery that a stretch of 4-7 amino acids in the APP juxtamembrane region, within the Aβ sequence (residues 17-23, Aβ numbering), is an inhibitory domain for γ-secretase cleavage that appears to work
COMMENT The new study by Chow and colleagues describes evidence that the combination of partial reductions in β-secretase and γ-secretase are effective in lowering Aβ production and deposition and preventing cognitive deficits in mice. This happens without the de
COMMENT This is an excellent study that describes missing pieces in the puzzle of γ-secretase: the existence of intervening peptides generated during the formation of Aβ and the APP intracellular domain (AICD). These peptides had been hypothesized for years but h
COMMENT This paper is on how blocking Aβ production may help treat traumatic brain injury. With respect to β-secretase, this was studied using BACE1 knockout mice, but with respect to γ- secretase, an inhibitor (DAPT) was used. The results look promising and sugg
COMMENT This paper is on the identification of a novel receptor that can regulate Aβ production. The receptor is a GPCR coupled to adenylate cyclase, but its natural ligand is unknown, and cAMP elevation by other means did not alter Aβ production. siRNA knockdown
COMMENT This paper reports the surprising identification by expression cloning of the prion protein (PrP) as a receptor for Aβ oligomers and the synaptotoxic consequences of this interaction. There is extensive evidence in support of these findings, and if confir
COMMENT This paper provides extensive and compelling evidence for β-APPs (shed from the cell surface by β-secretase) being a major agonist for the cell death receptor DR6, a key signaling pathway in the neuronal pruning that takes place during development. Finall
COMMENT This is an excellent study by the De Strooper lab, using a biochemical approach to identify proteins that associate with the γ-secretase complex. The work was rigorously done, with important controls to identify interactions specific to γ-secretase (e.g.,
COMMENT Sato et al. provide nice evidence that APP residues 618-660 can form a dimer...under conditions used for analysis by NMR. Under these conditions, the APP transmembrane domain appears to assume a helical conformation until the ε cleavage site, at which poi
COMMENT This report provides evidence that 1) disease-causing polyglutamine expansion in ataxin-1 can lead to increases in ATX1 assembly into complexes containing RNA-binding motif protein 17 (RBM17) and decreases in its assembly into complexes containing capicua
