Amyloid fibrillization is multistep process involving soluble oligomeric intermediates, including spherical oligomers and protofibrils. Amyloid oligomers have a common, generic structure, and they are intrinsically toxic to cells, even when formed from non-disease related proteins, which implies they also share a common mechanism of pathogenesis and toxicity. Here we report that soluble oligomers from several types of amyloids specifically increase lipid bilayer conductance regardless of the sequence, while fibrils and soluble low molecular weight species have no effect. The increase in membrane conductance occurs without any evidence of discrete channel or pore formation or ion selectivity. The conductance is dependent on the concentration of oligomers and can be reversed by anti-oligomer antibody. These results indicate that soluble oligomers from many types of amyloidogenic proteins and peptides increase membrane conductance in a conformation-specific fashion and suggest that this may represent the common primary mechanism of pathogenesis in amyloid-related degenerative diseases.Soluble amyloid oligomers are a common intermediate in the pathway for amyloid fibril formation and have been implicated as the primary toxic species of amyloids related to neurodegenerative disease (1-6). More recent reports indicate that soluble amyloid oligomers are intrinsically toxic even when they are formed from proteins that are not normally related to degenerative disease (3), and the toxic activity of soluble oligomers may be related to a common generic structure that they share (6). Although the primary mechanism of amyloid toxicity is not clear, the fact that different amyloids reside in either the cytosolic or extracellular compartments and the observation that cytosolic amyloid aggregates are toxic when applied externally to cells (6, 7) points to the cell plasma membrane as a potential primary target of amyloid pathogenesis. Indeed, there are many reports of membrane perturbations caused by amyloids like A␤ (8), but it isn't clear whether these effects are specific to soluble oligomers nor whether they are common to other types of amyloids. Here we report that homogeneous populations of spherical amyloid oligomers and protofibrils increase the conductivity of membranes by a non-channel mechanism. This effect is observed for all soluble oligomers tested regardless of protein sequence and is not observed for amyloid fibrils or soluble low molecular weight species, suggesting that the increase in membrane conductivity may be a primary common mechanism of amyloid oligomer pathogenesis. MATERIALS AND METHODSPeptide Synthesis-Peptide synthesis: A␤ peptides, prion 106 -126, and IAPP 1 were synthesized by fluoren-9-ylmethoxy carbonyl chemistry using a continuous flow semiautomatic instrument as described previously (9). The purity was checked by analytical reverse phase-high performance liquid chromatography and by electrospray mass spectrometry. Polyglutamine KKQ40KK was a gift from Dr. Ronald Wetzel, and ␣-synuclein was a gif...

Human processed lipoaspirate (PLA) cells are multipotent stem cells, capable of differentiating into multiple mesenchymal lineages (bone, cartilage, fat, and muscle). To date, differentiation to nonmesodermal fates has not been reported. This study demonstrates that PLA cells can be induced to differentiate into early neural progenitors, which are of an ectodermal origin. Undifferentiated cultures of human PLA cells expressed markers characteristic of neural cells such as neuron-specific enolase (NSE), vimentin, and neuron-specific nuclear protein (NeuN). After 2 weeks of treatment of PLA cells with isobutylmethylxanthine, indomethacin, and insulin, about 20 to 25 percent of the cells differentiated into cells with typical neural morphologic characteristics, accompanied by increased expression of NSE, vimentin, and the nerve-growth factor receptor trk-A. However, induced PLA cells did not express the mature neuronal marker, MAP, or the mature astrocyte marker, GFAP. It was also found that neurally induced PLA cells displayed a delayed-rectifier type K+ current (an early developmental ion channel) concomitantly with morphologic changes and increased expression of neural-specific markers. The authors concluded that human PLA cells might have the potential to differentiate in vitro into cells that represent early progenitors of neurons and/or glia.