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Anti-Aβ antibodies are important tools for identifying structural features of aggregates of the Aβ peptide and are used in many aspects of Alzheimer’s disease (AD) research. Our laboratory recently reported the generation of a polyclonal antibody, pAb 2AT-L , that is moderately selective for oligomeric Aβ over monomeric and fibrillar Aβ and recognizes the diffuse peripheries of Aβ plaques in AD brain tissue but does not recognize the dense fibrillar plaque cores. This antibody was generated against 2AT-L, a structurally defined Aβ oligomer mimic composed of three Aβ-derived β-hairpins arranged in a triangular fashion and covalently stabilized with three disulfide bonds. In the current study, we set out to determine if pAb 2AT-L is neuroprotective against toxic aggregates of Aβ and found that pAb 2AT-L protects human iPSC-derived neurons from Aβ 42 -mediated toxicity at molar ratios as low as 1:100 antibody to Aβ 42 , with a ratio of 1:25 almost completely rescuing cell viability. Few other antibodies have been reported to exhibit neuroprotective effects at such low ratios of antibody to Aβ. ThT and TEM studies indicate that pAb 2AT-L delays but does not completely inhibit Aβ 42 fibrillization at sub-stoichiometric ratios. The ability of pAb 2AT-L to inhibit Aβ 42 toxicity and aggregation at sub-stoichiometric ratios suggests that pAb 2AT-L binds toxic Aβ 42 oligomers and does not simply sequester monomeric Aβ 42 . These results further suggest that toxic oligomers of Aβ 42 share significant structural similarities with 2AT-L.

Amyloid formation is implicated in more than 20 human diseases, yet the mechanism by which fibrils form is not well understood. We use 2D infrared spectroscopy and isotope labeling to monitor the kinetics of fibril formation by human islet amyloid polypeptide (hIAPP or amylin) that is associated with type 2 diabetes. We find that an oligomeric intermediate forms during the lag phase with parallel β-sheet structure in a region that is ultimately a partially disordered loop in the fibril. We confirm the presence of this intermediate, using a set of homologous macrocyclic peptides designed to recognize β-sheets. Mutations and molecular dynamics simulations indicate that the intermediate is on pathway. Disrupting the oligomeric β-sheet to form the partially disordered loop of the fibrils creates a free energy barrier that is the origin of the lag phase during aggregation. These results help rationalize a wide range of previous fragment and mutation studies including mutations in other species that prevent the formation of amyloid plaques.

Antibodies that target the β-amyloid peptide (Aβ) and its associated assemblies are important tools in Alzheimer’s disease research and have emerged as promising Alzheimer’s disease therapies. This paper reports the creation and characterization of a triangular Aβ trimer mimic composed of Aβ17–36 β-hairpins and the generation and study of polyclonal antibodies raised against the Aβ trimer mimic. The Aβ trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the Aβ trimer mimic shares characteristics with oligomers of full-length Aβ. X-ray crystallography elucidates the structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer. SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution. Cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Immunostaining studies on brain slices from people who lived with Alzheimer’s disease and people who lived with Down syndrome reveal that the polyclonal antibodies raised against the Aβ trimer mimic recognize pathological features including different types of Aβ plaques and cerebral amyloid angiopathy.

Anti-A[beta] antibodies are important tools for identifying structural features of aggregates of the A[beta] peptide and are used in many aspects of Alzheimer's disease (AD) research. Our laboratory recently reported the generation of a polyclonal antibody, pAb.sub.2AT-L, that is moderately selective for oligomeric A[beta] over monomeric and fibrillar A[beta] and recognizes the diffuse peripheries of A[beta] plaques in AD brain tissue but does not recognize the dense fibrillar plaque cores. This antibody was generated against 2AT-L, a structurally defined A[beta] oligomer mimic composed of three A[beta]-derived [beta]-hairpins arranged in a triangular fashion and covalently stabilized with three disulfide bonds. In the current study, we set out to determine if pAb.sub.2AT-L is neuroprotective against toxic aggregates of A[beta] and found that pAb.sub.2AT-L protects human iPSC-derived neurons from A[beta].sub.42 -mediated toxicity at molar ratios as low as 1:100 antibody to A[beta].sub.42, with a ratio of 1:25 almost completely rescuing cell viability. Few other antibodies have been reported to exhibit neuroprotective effects at such low ratios of antibody to A[beta]. ThT and TEM studies indicate that pAb.sub.2AT-L delays but does not completely inhibit A[beta].sub.42 fibrillization at sub-stoichiometric ratios. The ability of pAb.sub.2AT-L to inhibit A[beta].sub.42 toxicity and aggregation at sub-stoichiometric ratios suggests that pAb.sub.2AT-L binds toxic A[beta].sub.42 oligomers and does not simply sequester monomeric A[beta].sub.42 . These results further suggest that toxic oligomers of A[beta].sub.42 share significant structural similarities with 2AT-L.

The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β 2 -microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles. A family of robust β-sheet macrocycles that can display a variety of heptapeptide sequences from different amyloid proteins is introduced. These amyloid β-sheet mimics can be tailored to antagonize aggregation of the proteins, thereby reducing the toxicity associated with diseases such as Alzheimer's.

Antibiotics that use novel mechanisms are needed to combat antimicrobial resistance 1 – 3 . Teixobactin 4 represents a new class of antibiotics with a unique chemical scaffold and lack of detectable resistance. Teixobactin targets lipid II, a precursor of peptidoglycan 5 . Here we unravel the mechanism of teixobactin at the atomic level using a combination of solid-state NMR, microscopy, in vivo assays and molecular dynamics simulations. The unique enduracididine C-terminal headgroup of teixobactin specifically binds to the pyrophosphate-sugar moiety of lipid II, whereas the N terminus coordinates the pyrophosphate of another lipid II molecule. This configuration favours the formation of a β-sheet of teixobactins bound to the target, creating a supramolecular fibrillar structure. Specific binding to the conserved pyrophosphate-sugar moiety accounts for the lack of resistance to teixobactin 4 . The supramolecular structure compromises membrane integrity. Atomic force microscopy and molecular dynamics simulations show that the supramolecular structure displaces phospholipids, thinning the membrane. The long hydrophobic tails of lipid II concentrated within the supramolecular structure apparently contribute to membrane disruption. Teixobactin hijacks lipid II to help destroy the membrane. Known membrane-acting antibiotics also damage human cells, producing undesirable side effects. Teixobactin damages only membranes that contain lipid II, which is absent in eukaryotes, elegantly resolving the toxicity problem. The two-pronged action against cell wall synthesis and cytoplasmic membrane produces a highly effective compound targeting the bacterial cell envelope. Structural knowledge of the mechanism of teixobactin will enable the rational design of improved drug candidates. Using a combination of methods, the mechanism of the antibiotic teixobactin is revealed.

The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of [beta]-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the [beta]-structures presents a challenge to developing a model system of [beta]-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust [beta]-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid [beta]-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-[beta] peptide associated with Alzheimer's disease, [beta](2)-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

Anti-Aβ antibodies are important tools for identifying structural features of aggregates of the Aβ peptide and are used in many aspects of Alzheimer's disease (AD) research. Our laboratory recently reported the generation of a polyclonal antibody, pAb2AT-L, that is moderately selective for oligomeric Aβ over monomeric and fibrillar Aβ and recognizes the diffuse peripheries of Aβ plaques in AD brain tissue but does not recognize the dense fibrillar plaque cores. This antibody was generated against 2AT-L, a structurally defined Aβ oligomer mimic composed of three Aβ-derived β-hairpins arranged in a triangular fashion and covalently stabilized with three disulfide bonds. In the current study, we set out to determine if pAb2AT-L is neuroprotective against toxic aggregates of Aβ and found that pAb2AT-L protects human iPSC-derived neurons from Aβ42-mediated toxicity at molar ratios as low as 1:100 antibody to Aβ42, with a ratio of 1:25 almost completely rescuing cell viability. Few other antibodies have been reported to exhibit neuroprotective effects at such low ratios of antibody to Aβ. ThT and TEM studies indicate that pAb2AT-L delays but does not completely inhibit Aβ42 fibrillization at sub-stoichiometric ratios. The ability of pAb2AT-L to inhibit Aβ42 toxicity and aggregation at sub-stoichiometric ratios suggests that pAb2AT-L binds toxic Aβ42 oligomers and does not simply sequester monomeric Aβ42. These results further suggest that toxic oligomers of Aβ42 share significant structural similarities with 2AT-L.