Amyloid inhibition by molecular chaperones in vitro can be translated to Alzheimer's pathology in vivo

Abstract

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. Approaches to treat Alzheimer's disease have not yet resulted in an effective treatment, suggesting that alternative strategies may be useful. Here, we discuss new treatment approaches based on molecular chaperones that inhibit amyloid-β (Aβ) aggregation by different microscopic mechanisms of action. 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. 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. 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. Hence, specific modulation of chaperone activity represents a promising new strategy for treatment of neurodegenerative disorders.