The Structural Basis For Increased Toxicity of Pathological AB42:AB40 Ratios in Alzheimer’s Disease



Kris Pauwels1, Thomas L. Williams2, Kyle L. Morris2, Wim Jonckheere3,4, Annelies Vandersteen3,4, Geoff Kelly1, Joost Schymkowitz3,4, Frederic Rousseau3,4, Annalisa Pastore1, Louise C. Serpell2, and Kerensa Broersen3,4


  1. Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA (UK)
  2. School of Life Sciences, University of Sussex, Falmer, East Sussex, BN1 9QJ (UK)
  3. Switch Laboratory, Flanders Institute for Biotechnology (VIB), Pleinlaan 2, 1050, Brussels (Belgium)
  4. Vrije Universiteit Brussel (VUB), Pleinlaan 2, 1050, Brussels (Belgium)


The beta-amyloid peptide (Aβ) is directly related to neurotoxicity in Alzheimer′s disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an Aβ42:Aβ40 ratio of ~1:9. This ratio is often shifted to a higher percentage of Aβ42 in brains of patients with familial AD and has recently been shown to lead to increased synaptoxicity. The molecular basis for this phenomenon is unclear. Whilst aggregation characteristics of Aβ40 and Aβ42 individually are well-established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant Aβ42:Aβ40 ratios by several techniques. We show that Aβ40 and Aβ42 directly interact and modify each other′s behavior. The structures of monomeric and fibrillar assemblies formed from Aβ40 and Aβ42 mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of Aβ40 and Aβ42 influences the aggregation kinetics by altering the pattern of oligomer formation as evidenced by a unique combination of solution nuclear magnetic resonance spectroscopy, high molecular weight mass spectrometry and cross-seeding experiments. We relate these observations to the observed enhanced toxicity of relevant ratios of Aβ42:Aβ40 in synaptotoxicity assays and in AD patients.

CovalX Technology Used (Click each option to learn more)



CAβ ratios were subjected to cross-linking with gluteraldehyde and then prepared using a phosphate buffered saline buffer. The samples were mixed with a sinapic acid matrix (10 mg/ml) in acetronitrile/water (1:1, v/v) and TFA 0.1% before being spotted onto a MALDI plate. The plate was analyzed using a mass spectrometer that had been modified with a CovalX HM2 detection system.



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