A turn for the worse: A β β-hairpins in Alzheimer's disease

Bioorg Med Chem. 2024 Apr 10;105:117715. doi: 10.1016/j.bmc.2024.117715. Online ahead of print.ABSTRACTAmyloid-β (Aβ) oligomers are a cause of neurodegeneration in Alzheimer's disease (AD). These soluble aggregates of the Aβ peptide have proven difficult to study due to their inherent metastability and heterogeneity. Strategies to isolate and stabilize homogenous Aβ oligomer populations have emerged such as mutations, covalent cross-linking, and protein fusions. These strategies along with molecular dynamics simulations have provided a variety of proposed structures of Aβ oligomers, many of which consist of molecules of Aβ in β-hairpin conformations. β-Hairpins are intramolecular antiparallel β-sheets composed of two β-strands connected by a loop or turn. Three decades of research suggests that Aβ peptides form several different β-hairpin conformations, some of which are building blocks of toxic Aβ oligomers. The insights from these studies are currently being used to design anti-Aβ antibodies and vaccines to treat AD. Research suggests that antibody therapies designed to target oligomeric Aβ may be more successful at treating AD than antibodies designed to target linear epitopes of Aβ or fibrillar Aβ. Aβ β-hairpins are good epitopes to use in antibody development to selectively target oligomeric Aβ. This review summarizes the research on β-hairpins in Aβ peptides and discusses the relevance of this conformation in AD pathogenesis and drug development.PM...
Source: Bioorganic and Medicinal Chemistry - Category: Chemistry Authors: Source Type: research