Therapeutics in Alzheimer's and prion diseases.
There is increasing recognition that numerous neurodegenerative conditions have the same underlying pathogenetic mechanism, namely a change in protein conformation, where the beta-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-beta peptide (sA beta) to A beta plaques; while in the prionoses the critical event is the conversion of normal prion protein, PrP(C), to the disease-associated form, PrP(Sc). 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 'beta-sheet breakers' that directly target the abnormal conformational change both for A beta- and PrP(Sc)-related deposits. In addition, immune system activation can serve as beta-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.
Wisniewski
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Department of Neurology, New York University Medical Center, 550 First Avenue TH 427, New York, NY 10016, USA. thomas.wisniewski@med.nyu.edu
Brown
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DR
Sigurdsson
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D000544:Alzheimer Disease / Q000276:immunology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D017096:Prion Diseases / Q000628:therapy*; D017433:Protein Structure, Secondary; D014614:Vaccines, Synthetic / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D014614:Vaccines, Synthetic