Missense mutations in the human presenilin-1 (PS1) gene, which is found on chromosome 14, cause early-onset familial Alzheimer's disease (FAD). FAD-linked PS1 variants alter proteolytic processing of the amyloid precursor protein and cause an increase in vulnerability to apoptosis induced by various cell stresses. However, the mechanisms responsible for these phenomena are not clear. Here we report that mutations in PS1 affect the unfolded-protein response (UPR), which responds to the increased amount of unfolded proteins that accumulate in the endoplasmic reticulum (ER) under conditions that cause ER stress. PS1 mutations also lead to decreased expression of GRP78/Bip, a molecular chaperone, present in the ER, that can enable protein folding. Interestingly, GRP78 levels are reduced in the brains of Alzheimer's disease patients. The downregulation of UPR signalling by PS1 mutations is caused by disturbed function of IRE1, which is the proximal sensor of conditions in the ER lumen. Overexpression of GRP78 in neuroblastoma cells bearing PS1 mutants almost completely restores resistance to ER stress to the level of cells expressing wild-type PS1. These results show that mutations in PS1 may increase vulnerability to ER stress by altering the UPR signalling pathway.

Chemical ReviewsREVIEW publication of the excellent review on the Strecker reaction by Gr€ oger, 3 the section concerning the cyanation of imines only covers the literature from mid-2002 to the present. For a comprehensive treatment of asymmetric propargylation of CdN compounds, readers should consult the review of the area by Tomioka. 8

We have developed an efficient system for triphase reactions using a microchannel reactor. Using this system, we conducted hydrogenation reactions that proceeded smoothly to afford the desired products quantitatively within 2 minutes for a variety of substrates. The system could also be applied to deprotection reactions. We could achieve an effective interaction between hydrogen, substrates, and a palladium catalyst using extremely large interfacial areas and the short path required for molecular diffusion in the very narrow channel space. This concept could be extended to other multiphase reactions that use gas-phase reagents such as oxygen and carbon dioxide.

A Lewis acid-surfactant-combined catalyst (LASC) has been developed and applied to Lewis acidcatalyzed organic reactions in water. LASCs are composed of water-stable Lewis acidic cations such as scandium and anionic surfactants such as dodecyl sulfate and dodecanesulfonate and are easily prepared. These catalysts have been successfully used for various typical carbon-carbon bond-forming reactions such as aldol, allylation, and Mannich-type reactions in water. Furthermore, the results of aldol reactions in various solvents show that water is the best solvent for the LASC-catalyzed reactions. A preliminary kinetic study of the aldol reaction showed that the initial rate in water was 1.3 × 10 2 times higher than that in dichloromethane. In the workup procedure, it was demonstrated that centrifugation of the reaction mixture led to phase separation without addition of any organic solvents. The LASCs was found to form stable colloidal dispersions rapidly in the presence of reaction substrates in water, even when the substrates are solid. The characterization of the colloidal particles has been carried out by means of dynamic light scattering, light microscopy, transmission electron microscopy, and atomic force microscopy. These observations revealed the size of ∼1 µm and the spherical shape of the particles. It was suggested that most of the substrates and catalyst molecules were concentrated in the spherical particles, which acted as a hydrophobic reaction environment and enabled the rapid organic reactions in water. In light of the increased demand for reduction of organic solvents in industry, the surfactantaided Lewis acid catalysis described here may have practical consequences in organic synthesis.