Aggregation and toxicity

Protein aggregation is central to most neurodegenerative diseases, as shown by familial case studies and by animal models. A modified ‘amyloid cas-cade’ hypothesis for Alzheimer’s disease states that prefibrillar oligomers, also called amyloid-b-derived diffusible ligands or globular oligomers, are the responsible toxic agent. It has been proposed that these oligomeric spe-cies, as shown for amyloid-b, b2 -microglobulin or prion fragments, exert toxicity by forming pores in membranes, initiating a cascade of detrimental events for the cell. ...

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A yeast model was generated to study the mechanisms and phenotypical repercussions of expression of a-synuclein as well as the coexpression of protein tau. The data show that aggregation ofa-synuclein is a nucleation– elongation process initiated at the plasma membrane. Aggregation is con-sistently enhanced by dimethyl sulfoxide, which is known to increase the level of phospholipids and membranes in yeast cells.

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Beta-amyloid (1–40) (Abeta), the main component of senile plaques seen in the brains of Alzheimer’s disease patients, was found to be toxic both as fibrils and smaller soluble globular aggregates. The hydrolytic properties of Abeta, a new biochemical activity described previously [Brzyska M, Bacia A & Elbaum D (2001)Eur J Biochem268, 3443–3454], may contribute to its overall toxicity.

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After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington’s disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis.

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Human stefin B, from the family of cystatins, is used as a model amyloido-genic protein in studies of the mechanism of amyloid fibril formation and related cytotoxicity. Interaction of the protein’s prefibrillar oligo-mers⁄aggregates with predominantly acidic phospholipid membranes is known to correlate with cellular toxicity.

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Amyloid-b(Ab) aggregation and amyloid formation are key pathological features of Alzheimer’s disease, and are considered to be two of the major contributing factors to neurodegeneration and dementia. Identification of small molecule inhibitors that are orally available, have low toxicity and high central nervous system bioavailability is one approach to the potential development of a disease-modifying treatment for Alzheimer’s disease.

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The amyloidbpeptide (Ab) with 39–42 residues is the major component of amyloid plaques found in brains of Alzheimer’s disease patients, and solu-ble oligomeric peptide aggregates mediate toxic effects on neurons. The Ab aggregation involves a conformational change of the peptide structure to b-sheet.

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Alzheimer’s disease (AD) is an age-related, progressive degenerative dis-order that is characterized by synapse and neuron loss in the brain and the accumulation of protein-containing deposits (referred to as ‘senile plaques’) and neurofibrillary tangles. Insoluble amyloid b-peptide (Ab) fibrillar aggregates found in extracellular plaques have long been thought to cause the neurodegenerative cascades of AD.

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