The aggregation (fibril formation) of amyloid beta-protein (Abeta) is considered to be a crucial step in the etiology of Alzheimer's disease (AD). The inhibition of Abeta aggregation and/or decomposition of fibrils formed in aqueous solution by small compounds have been studied extensively for the prevention and treatment of AD. However, recent studies suggest that Abeta aggregation also occurs in lipid rafts mediated by a cluster of monosialoganglioside GM1. This study examined the effects of representative compounds on Abeta aggregation and fibril destabilization in the presence of GM1-containing raft-like liposomes. Among the compounds tested, nordihydroguaiaretic acid (NDGA), rifampicin (RIF), tannic acid (TA), and quercetin (QUE) showed strong fibrillization inhibitory activity. NDGA and RIF inhibited the binding of Abeta to GM1 liposomes by competitively binding to the membranes and/or direct interaction with Abeta in solution, thus at least partly preventing fibrils from forming. Coincubation of Abeta with NDGA, RIF, and QUE in the presence of GM1 liposomes resulted in elongate particles, whereas the presence of TA yielded protofibrillar structures. TA and RIF also destabilized fibrils. The most potent NDGA prevented Abeta-induced toxicity in PC12 cells by inhibiting Abeta accumulation. Furthermore, a comparison of the inhibitory effects of various compounds between aqueous-phase and GM1-mediated aggregation of Abeta suggested that the two aggregation processes are not identical.
Using 4-month-old fetal bovine tissue, the properties of the tibia epiphyseal cartilage matrix vesicles, a type of endochondral ossification tissue, were compared with those from tracheal cartilage. The matrix vesicle fractions, obtained by collagenase digestion and differential centrifugation, were subjected to sucrose-density-gradient centrifugation. Alkaline phosphatase activity, protease activity, and lacatate dehydrogenase activity were assayed for the marker enzyme of the matrix vesicles. Matrix vesicles containing alkaline phosphatase, metalloprotease, and lacatate dehydrogenase were found in the tibia epiphyseal cartilage at a density of 1.11 g/ml. In surprising contrast, we also found matrix vesicle-like vesicles with a high density of 1.24 g/ml in the tracheal cartilage. These also contained alkaline phosphatase and lactate dehydrogenase, but not metalloprotease. The electrophoretic profiles of the lactate dehydrogenase isoenzymes from the matrix vesicle and matrix vesicle-like vesicles were identical with those of chondrocyte cytosolic lactate dehydrogenase. Aldolase, aspartate: 2-oxoglutarate aminotransferase, alanine: 2-oxoglutarate aminotransferase, glucose-6-phosphatase, glutamate dehydrogenase, catalase, and cytosolic enzymes except for lactate dehydrogenase were not detected in these vesicles. These results suggest the presence of a mechanism for specific uptake of cytosolic lactate dehydrogenase in both vesicles. In this study, a new type of matrix vesicles without protease was found in the tracheal cartilage, a kind of permanent cartilage, but not in the tibia epiphyseal cartilage, which is replaced by bone tissue.
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