Structural polymorphism and cytotoxicity of brain-derived β-amyloid extracts

To date, more than 37 amyloidogenic proteins have been found to form toxic aggregates that are implicated in the progression of numerous debilitating protein misfolding diseases including Alzheimer's disease (AD). Extensive literature highlights the role of beta-amyloid (A beta) aggregates in causing excessive neuronal cell loss in the brains of AD patients. In fact, major advances in our understanding of A beta aggregation process, including kinetics, toxicity, and structures of fibrillar aggregates have been revealed by examining in vitro preparations of synthetic A beta peptides. However, ongoing research shows that brain-derived A beta aggregates have specific characteristics that distinguish them from in vitro prepared species. Notably, the molecular structures of amyloid fibrils grown in the human brain were found to be markedly different than synthetic A beta fibrils. In addition, recent findings report the existence of heterogeneous A beta proteoforms in AD brain tissue in contrast to synthetically produced full-length aggregates. Despite their high relevance to AD progression, brain-derived A beta species are less well-characterized compared with synthetic aggregates. The aim of this review is to provide an overview of the literature on brain-derived A beta aggregates with particular focus on recent studies that report their structures as well as pathological roles in AD progression. The main motivation of this review is to highlight the importance of utilizing brain-derived amyloids for characterizing the structural and toxic effects of amyloid species. With this knowledge, brain-derived aggregates can be adopted to identify more relevant drug targets and validate potent aggregation inhibitors toward designing highly effective therapeutic strategies against AD.

Automated summary

To date, more than 37 amyloidogenic proteins have been found to form toxic aggregates implicated in the progression of various protein misfolding diseases, including Alzheimer's disease (AD). However, brain-derived A beta aggregates exhibit distinct characteristics compared to synthetic A beta fibrils, and there is a lack of comprehensive characterization of these species. This review aims to provide an overview of recent studies on the structures and pathological roles of brain-derived A beta aggregates, emphasizing their importance in understanding AD progression and developing effective therapeutic strategies.