Anti-Aggregating Antibodies, a New Approach Towards Treatment of Conformational Diseases
Abstract:More and more evidence shows that Alzheimer's and prion-related diseases belong to the family of conformational diseases characterized by protein self-association and tissue deposition as amyloid fibrils. Regardless of the nature of the protein constituent, all forms of amyloid are stable assemblies based on noncovalent interactions between subunits of crossed β-sheet structure. Understanding the mechanism and molecular details of the pathological conformational conversion of amyloidogenic proteins may be of importance to the development of approaches towards prevention and treatment of such diseases. We previously found that monoclonal antibodies (mAbs) interact at strategic sites where protein unfolding is initiated, thereby stabilizing the protein and preventing further precipitation. Indeed, site-directed mAbs raised against the N-terminal region of Alzheimer's β-peptide (AβP) disaggregate AβP fibrils, restore peptide solubility and prevent its neurotoxic effects. Similarly, selected mAbs raised against the human prion peptide 106-126 modulate conformational changes occurring in the prion peptide exposed to aggregating conditions, preventing its aggregation and related neurotoxicity on cultivated neural-like cells. All these data and related procedures bring more attention to the immunological concept in the treatment of conformational diseases, and the recent performance of such antibodies in transgenic mice, as a model for human diseases, suggests the development of vaccination approaches against such diseases.
Document Type: Review Article
Publication date: October 1, 2002
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