7U4P

Covalently stabilized triangular trimer composed of Abeta17-36 beta-hairpins

This is a non-PDB format compatible entry.

Summary for 7U4P

• Entry DOI: 10.2210/pdb7u4p/pdb
• Descriptor: Amyloid-beta 17-36 peptide (2 entities in total)
• Functional Keywords: abeta oligomer, beta-hairpin, trimer, dodecamer, alzheimer's disease, de novo protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 6643.88

Authors

Kreutzer, A.G.,Haerianardakani, S.,Nowick, J.S. (deposition date: 2022-02-28, release date: 2023-03-15, Last modification date: 2024-03-27)

Primary citation

Kreutzer, A.G.,Parrocha, C.M.T.,Haerianardakani, S.,Guaglianone, G.,Nguyen, J.T.,Diab, M.N.,Yong, W.,Perez-Rosendahl, M.,Head, E.,Nowick, J.S.
Antibodies Raised Against an A beta Oligomer Mimic Recognize Pathological Features in Alzheimer's Disease and Associated Amyloid-Disease Brain Tissue.
Acs Cent.Sci., 10:104-121, 2024

PubMed Abstract: 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 Aβ 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.

PubMed: 38292607
DOI: 10.1021/acscentsci.3c00592

Experimental method

X-RAY DIFFRACTION (1.803 Å)