17,24,25 Targeting specific nucleation events, rather than overall aggregation, has hence been suggested as a more promising approach in the search for efficient AD therapeutics. 16,23 As accumulating evidence assigns pre-fibrillar oligomeric species, and not the fibril structure as such, as the most toxic species, prevention of formation of Aβ oligomers should minimize toxic effects. 16,22 This was found to be the dominant mechanism in Aβ40 and Aβ42 (40 and 42 residue, respectively, Aβ isoforms) self-assembly, and to be the major source of the generation of presumably toxic oligomers ( Fig. The fibril surface was found to play a crucial role in catalyzing the formation of new nucleation units during Aβ aggregation, in a process referred to as secondary nucleation. The explanation for the lack of effective treatments might, however, rather be found in the details of the molecular mechanisms of the interventions. The drastic rate of failure of these attempts in clinical trials has led to questioning of the amyloid cascade hypothesis in general. 21 The main focus of these trials has been to decrease the total Aβ plaque load by inhibiting Aβ aggregation in general, or to reduce the overall Aβ production by modulating Aβ precursor protein (APP) cleavage. Since then, many therapeutic attempts have targeted Aβ production and aggregation, either using antibody-based immunotherapies or enzyme inhibition. 17 The amyloid cascade hypothesis was put forward more than 20 years ago, 18–20 pinpointing the misfolding and aggregation of the amyloid-β peptide as the cause of AD, preceding other characteristics such as tau pathology. Introduction Alzheimer's disease (AD) is the most prominent neurodegenerative disease affecting an increasing number of people worldwide due to the rising elderly society. Hence, specific modulation of chaperone activity represents a promising new strategy for treatment of neurodegenerative disorders. Interestingly, recent immunotherapy advances, which have demonstrated significant improvements in clinical phase III trials, have used antibodies that selectively act against Aβ oligomer formation, supporting the notion that specific inhibition of Aβ neurotoxicity is more rewarding than reducing overall amyloid fibril formation. The inhibition of Aβ oligomer generation in vitro seemingly correlates with the effects of treatment, giving indirect clues about the molecular mechanisms present in vivo. Molecular chaperones that specifically target secondary nucleation reactions during Aβ aggregation in vitro – a process closely associated with Aβ oligomer generation – have shown promising results in animal treatment studies. Here, we discuss new treatment approaches based on molecular chaperones that inhibit amyloid-β (Aβ) aggregation by different microscopic mechanisms of action. Approaches to treat Alzheimer's disease have not yet resulted in an effective treatment, suggesting that alternative strategies may be useful. Molecular chaperones are important components in the cellular quality-control machinery and increasing evidence points to potential new roles for them as suppressors of amyloid formation in neurodegenerative diseases, such as Alzheimer's disease.
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