Poster Presentation The 46th Lorne Conference on Protein Structure and Function 2021

Diversion of Aβ42 to non-toxic aggregates by a monomer sequestration mechanism (#303)

Sarah R Ball 1 , Julius S P Adamson 2 , Michael A Sullivan 1 , Manuela R Zimmerman 3 , Victor Lo 1 , Maximo Sanz Hernandez 1 , Frank Jiang 2 , Ann Kwan 4 , Eryn L Werry 1 , Tuomas P J Knowles 3 , Michael Kassiou 1 , Georg Meisl 3 , Matthew H Todd 5 , Peter J Rutledge 2 , Margaret Sunde 1
  1. Discipline of Pharmacology, University of Sydney, Sydney, Australia
  2. School of Chemistry, University of Sydney, Sydney, Australia
  3. Centre for Misfolding Diseases, Department of Chemistry, , University of Cambridge, Cambridge, UK
  4. School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
  5. School of Pharmacy, University College London, London, UK

The amyloid-β peptide, the main protein component of amyloid plaques in Alzheimer’s disease, plays a key role in the neurotoxicity associated with the condition via the formation of small toxic oligomer species and the disruption of calcium and glutamate homeostasis. The lack of therapeutic benefit associated with removal of mature amyloid-β fibrils has focused attention on the toxic oligomeric species formed during the process of fibril assembly. Here, we have synthesised and tested a series of new compounds that divert the monomeric form of the amyloid-β peptide into amorphous aggregates that are not toxic to differentiated SH-SY5Y cells in vitro. This diversion effectively prevents the formation of damaging oligomers. The activity of the compounds has been monitored using seeded and unseeded thioflavin T fluorescence assays and NMR and verified using transmission electron microscopy. Quantitative analysis of the effects of these compounds on the assembly pathway identifies rapid monomer sequestration as the underlying neuroprotective mechanism. The ability to specifically target the monomer form of amyloid-β allows for further understanding of the impact of the multiple species formed between peptide biogenesis and plaque deposition.