Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2022 Feb 25

PMID 35213141

Authors

Kate J McKnelly

Adam G Kreutzer

William J Howitz

Katelyn Haduong

Stan Yoo

Candace Hart

James S Nowick

Affiliations

Soon will be listed here.

Abstract

Familial Alzheimer's disease (FAD) is associated with mutations in the β-amyloid peptide (Aβ) or the amyloid precursor protein (APP). FAD mutations of Aβ were incorporated into a macrocyclic peptide that mimics a β-hairpin to study FAD point mutations K16N, A21G, E22Δ, E22G, E22Q, E22K, and L34V and their effect on assembly, membrane destabilization, and cytotoxicity. The X-ray crystallographic structures of the four E22 mutant peptides reveal that the peptides assemble to form the same compact hexamer. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) experiments reveal that the mutant FAD peptides assemble as trimers or hexamers, with peptides that have greater positive charge assembling as more stable hexamers. Mutations that increase the positive charge also increase the cytotoxicity of the peptides and their propensity to destabilize lipid membranes.

Citing Articles

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

Ruttenberg S, Nowick J Bioorg Med Chem. 2024; 105:117715.

PMID: 38615460 PMC: 11876106. DOI: 10.1016/j.bmc.2024.117715.

Real-time detection of 20 amino acids and discrimination of pathologically relevant peptides with functionalized nanopore.

Zhang M, Tang C, Wang Z, Chen S, Zhang D, Li K Nat Methods. 2024; 21(4):609-618.

PMID: 38443507 PMC: 11009107. DOI: 10.1038/s41592-024-02208-7.

β-Hairpin Alignment Alters Oligomer Formation in Aβ-Derived Peptides.

Ruttenberg S, Kreutzer A, Truex N, Nowick J Biochemistry. 2024; 63(2):212-218.

PMID: 38163326 PMC: 10795187. DOI: 10.1021/acs.biochem.3c00526.

A β-barrel-like tetramer formed by a β-hairpin derived from Aβ.

Samdin T, Jones C, Guaglianone G, Kreutzer A, Freites J, Wierzbicki M Chem Sci. 2023; 15(1):285-297.

PMID: 38131075 PMC: 10732006. DOI: 10.1039/d3sc05185d.

Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer's, Parkinson's, and Huntington's Diseases and Amyotrophic Lateral Sclerosis.

Ciurea A, Mohan A, Covache-Busuioc R, Costin H, Glavan L, Corlatescu A Int J Mol Sci. 2023; 24(13).

PMID: 37445986 PMC: 10341997. DOI: 10.3390/ijms241310809.

References

Kreutzer A, Yoo S, Spencer R, Nowick J . Stabilization, Assembly, and Toxicity of Trimers Derived from Aβ. J Am Chem Soc. 2016; 139(2):966-975. PMC: 5256483. DOI: 10.1021/jacs.6b11748. View

Nilsberth C, Westlind-Danielsson A, Eckman C, Condron M, Axelman K, Forsell C . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001; 4(9):887-93. DOI: 10.1038/nn0901-887. View

Pham J, Chim N, Goulding C, Nowick J . Structures of oligomers of a peptide from β-amyloid. J Am Chem Soc. 2013; 135(33):12460-7. PMC: 3787202. DOI: 10.1021/ja4068854. View

Hamilton J, Hillard C, Spector A, Watkins P . Brain uptake and utilization of fatty acids, lipids and lipoproteins: application to neurological disorders. J Mol Neurosci. 2007; 33(1):2-11. DOI: 10.1007/s12031-007-0060-1. View

Benilova I, Karran E, De Strooper B . The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes. Nat Neurosci. 2012; 15(3):349-57. DOI: 10.1038/nn.3028. View

Hatami A, Monjazeb S, Milton S, Glabe C . Familial Alzheimer's Disease Mutations within the Amyloid Precursor Protein Alter the Aggregation and Conformation of the Amyloid-β Peptide. J Biol Chem. 2017; 292(8):3172-3185. PMC: 5336154. DOI: 10.1074/jbc.M116.755264. View

Ciudad S, Puig E, Botzanowski T, Meigooni M, Arango A, Do J . Aβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage. Nat Commun. 2020; 11(1):3014. PMC: 7296003. DOI: 10.1038/s41467-020-16566-1. View

Selkoe D . Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001; 81(2):741-66. DOI: 10.1152/physrev.2001.81.2.741. View

Greenfield N . Using circular dichroism spectra to estimate protein secondary structure. Nat Protoc. 2007; 1(6):2876-90. PMC: 2728378. DOI: 10.1038/nprot.2006.202. View

10.

. 2020 Alzheimer's disease facts and figures. Alzheimers Dement. 2020; . DOI: 10.1002/alz.12068. View

11.

Yu L, Edalji R, Harlan J, Holzman T, Lopez A, Labkovsky B . Structural characterization of a soluble amyloid beta-peptide oligomer. Biochemistry. 2009; 48(9):1870-7. DOI: 10.1021/bi802046n. View

12.

Spencer R, Li H, Nowick J . X-ray crystallographic structures of trimers and higher-order oligomeric assemblies of a peptide derived from Aβ(17-36). J Am Chem Soc. 2014; 136(15):5595-8. PMC: 4004244. DOI: 10.1021/ja5017409. View

13.

Vadukul D, Vrancx C, Burguet P, Contino S, Suelves N, Serpell L . An evaluation of the self-assembly enhancing properties of cell-derived hexameric amyloid-β. Sci Rep. 2021; 11(1):11570. PMC: 8172837. DOI: 10.1038/s41598-021-90680-y. View

14.

Arias M, Vogel H . Fluorescence and Absorbance Spectroscopy Methods to Study Membrane Perturbations by Antimicrobial Host Defense Peptides. Methods Mol Biol. 2016; 1548:141-157. DOI: 10.1007/978-1-4939-6737-7_10. View

15.

Sciacca M, Kotler S, Brender J, Chen J, Lee D, Ramamoorthy A . Two-step mechanism of membrane disruption by Aβ through membrane fragmentation and pore formation. Biophys J. 2012; 103(4):702-10. PMC: 3443794. DOI: 10.1016/j.bpj.2012.06.045. View

16.

Kagan B, Thundimadathil J . Amyloid peptide pores and the beta sheet conformation. Adv Exp Med Biol. 2010; 677:150-67. DOI: 10.1007/978-1-4419-6327-7_13. View

17.

Demuro A, Parker I, Stutzmann G . Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem. 2010; 285(17):12463-8. PMC: 2857063. DOI: 10.1074/jbc.R109.080895. View

18.

Kreutzer A, Hamza I, Spencer R, Nowick J . X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an Aβ17-36 β-Hairpin. J Am Chem Soc. 2016; 138(13):4634-42. PMC: 4831588. DOI: 10.1021/jacs.6b01332. View

19.

Salveson P, Haerianardakani S, Thuy-Boun A, Kreutzer A, Nowick J . Controlling the Oligomerization State of Aβ-Derived Peptides with Light. J Am Chem Soc. 2018; 140(17):5842-5852. PMC: 6361387. DOI: 10.1021/jacs.8b02658. View

20.

Kreutzer A, Spencer R, McKnelly K, Yoo S, Hamza I, Salveson P . A Hexamer of a Peptide Derived from Aβ. Biochemistry. 2017; 56(45):6061-6071. PMC: 5689071. DOI: 10.1021/acs.biochem.7b00831. View