The progressive deposition of aggregated or polymerized beta amyloid (A beta) protein in senile plaques in the brain of Alzheimers disease sufferers is generally considered to be fundamental to the development of disease pathology. Although neurodegenerative properties have been demonstrated for a variety of multimeric forms of A beta, the precise identity of the neurotoxic species has been the topic of much debate. Initial in vitro studies reported neurotoxic properties for large A beta fibrils, although more recently it has emerged that much smaller oligomers are also toxic and, in cell culture systems, can be formed intracellularly. The term amyloid describes macroscopic birefringent tissue deposits of a number of abnormally folded proteins. Generically, amyloid formation is believed to serve no physiological function, often forms part of a pathological process and is, therefore, therapeutically attractive. A number of series of compounds have been reported which prevent the in vitro aggregation or polymerization of A beta. These have often arisen from compound bank screening rather than rational design based on target identification. Data suggest that there is neither a single monomeric or multimeric form of, nor a common site on, the A beta molecule to which all of these inhibitors bind. Inhibiting A beta aggregation remains a therapeutic target but future drug discovery will only follow a rational rather than irrational path when inhibitorA beta and A beta-A beta interactions and the cellular site(s) of oligomer(SLASH)fibril formation are more fully understood.
Keywords: oligomerization, Therapeutic Target, multimeric forms, amyloid protein, proteinase resistant structures, intraneuronal neurofibrillary tangles, senile plaque core, polymerization process, extracellular millieau, oligomer fibril formation, quasi elastic light scattering, hydrophobic residues, anti fibrillar activity, transthyretin tetramer
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