The accumulation of ␤-amyloid peptides (A␤) into senile plaques is one of the hallmarks of Alzheimer disease. Aggregated A␤ is toxic to cells in culture and this has been considered to be the cause of neurodegeneration that occurs in the Alzheimer disease brain. The discovery of compounds that prevent A␤ toxicity may lead to a better understanding of the processes involved and ultimately to possible therapeutic drugs. Low nanomolar concentrations of A␤1-42 and the toxic fragment A␤25-35 have been demonstrated to render cells more sensitive to subsequent insults as manifested by an increased sensitivity to formazan crystals following MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction. Formation of the toxic ␤-sheet conformation by A␤ peptides is increased by negatively charged membranes. Here we demonstrate that phloretin and exifone, dipolar compounds that decrease the effective negative charge of membranes, prevent association of A␤1-40 and A␤25-35 to negatively charged lipid vesicles and A␤ induced cell toxicity. These results suggest that A␤ toxicity is mediated through a nonspecific physicochemical interaction with cell membranes.␤-amyloid, the major constituent of senile plaques in Alzheimer disease patients (1) has been proposed to be the cause of the neurodegeneration that occurs in Alzheimer disease brains. A␤1-42, A␤1-40, and certain fragments, notably A␤25-35, are directly toxic to neuronal cell cultures at high micromolar concentrations (2-5). The observed cell death has been correlated with an effect of amyloid peptides on the membrane integrity as determined by lipid peroxidation (2). Furthermore, it has recently been shown that low nanomolar concentrations of A␤ peptides increase the susceptibility of the plasma membrane to additional insults (6).Substantial evidence has been provided suggesting that a crucial step for the formation of toxic A␤ is the transition of random coil to ␤-sheet conformation that is necessary for fibril aggregation. Those fibrils have been demonstrated to cause cell death (7-9). On the other hand studies with lipid vesicles demonstrated that formation of ␤-sheet structures is enhanced in the presence of negatively charged lipid vesicles (10-12). Decreasing the negative charge of a membrane may, therefore, result in a decrease in membrane association of A␤ peptides. Such a decrease in the negative charge of lipid membranes by a decrease in the membrane dipole potential has been demonstrated for phloretin, a lipophilic dipolar substance shown to decrease the membrane dipole potential (13-15).Here we demonstrate that phloretin and a structural analogue, exifone, not only reduce the association of toxic A␤ peptides with the membrane but also prevent A␤ toxicity to neuron-like PC12 cells. These results suggest that a physicochemical interaction of A␤ peptides with negatively charged membranes might be responsible for the toxic effect of A␤ to neuronal cells. MATERIALS AND METHODSMaterials. Rat PC12 pheochromocytoma cells were a gift from E. Sho...

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The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.

The posterolateral corner of the knee accommodating the fabella complex is of importance in orthopaedic surgery. Unfortunately, there is a lack of data in literature for clinical routine. Therefore, we investigated the fabella's characteristics, biomechanical nature, and present histologic details. Of special interest were the fabella's occurrence and position, calcium concentration as long-term load intake indicator, and the histology. Within our analysis, fabellae were found in 30.0% of all datasets, located on the upper part of the posterolateral femoral condyle. The region of fabella contact on this condyle showed a significantly lower calcium concentration than its surroundings. Histologically, the fabella showed no articular cartilage but a clearly distinguishable fabellofibular ligament that consisted of two bundles: one, as already described in literature inserted at the fibular tip, and another part newly described on the top of the lateral meniscus. In its role of stabilizing the soft tissue structures of the posterolateral knee, the fabella seems to serve as suspension for the ligaments evolving from its base. Even though a joint formation of any kind is unlikely, the presence of a fabella needs to be kept in mind during knee examination and any surgical procedures.