There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the β-sheet content is increased. In Alzheimer's disease, amyloid deposition in the form of neuritic plaques and congophilic angiopathy is driven by the conversion of normal soluble amyloid-β peptide (sAβ) to Aβ plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrPc, to the disease-associated form, PrPsc. This common theme in the pathogenesis of these disorders and the extracellular localization of the accumulating abnormal protein make them highly amenable to therapeutic approaches based on experimental manipulation of protein conformation and clearance. A number of different approaches under current development include drugs which affect the processing of the precursor proteins drugs the clearance of the amyloidogenic protein, and which inhibit or prevent the conformation change and immunological approaches. Particularly interesting are compounds termed ‘β-sheet breakers’ that directly target the abnormal conformational change both for Aβ- and PrPsc-related deposits. In addition, immune system activation can serve as β-sheet breakers and/or to increase the clearance of the disease-associated proteins. These conformation-based approaches appear to hold the best promise for therapies for this devastating group of disorders.

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