Fundamentals of protein misfolding, Amyloid-beta (Aβ) assembly and Alzheimer’s disease

John H. Viles (primary)
Sch of Biological & Chemical Sciences
Queen Mary
Mark D. Baker (secondary)
Blizard Institute
Barts and the London

Abstract

Alzheimer’s disease (AD) has a profound impact on healthy ageing. It is characterized by the accumulation of a small neuro-toxic peptide, amyloid-beta (Aβ) which forms fibrous plaques within the brain. Interestingly N-terminally truncated forms of Aβ constitute 20% of plaque load. Surprisingly very little is known about these truncated forms of Aβ. The PhD student will use a large tool-kit of biophysical and spectroscopic techniques to probe, the kinetics of fibre formation, fibre structure and lipid membrane interactions. In addition, electro-physiology will be used investigate ion channel formation to investigate the relationship between N-terminally truncated Aβ, cellular toxicity and AD pathology.


References

[1] Naslund, J.; Schierhorn, A.; Hellman, U.; Lannfelt, L.; Roses, A. D.; Tjernberg, L. O.; Silberring, J.; Gandy, S. E.; Winblad, B.; Greengard, P.; Nordstedt, C.; Terenius, L.
RELATIVE ABUNDANCE OF ALZHEIMER A-BETA AMYLOID PEPTIDE VARIANTS IN ALZHEIMER-DISEASE.
(1994) Proc of the Nat Acad of Sci. 91, 8378-8382

[2] Matheou CJ; Younan ND; Viles JH
Cu2+ accentuates distinct misfolding of Abeta(1-40) and Abeta(1-42) peptides, and potentiates membrane disruption.
(2015) Biochem J. 466, 233-242

[3] Bode DC, Baker MD, Viles JH
Ion Channel Formation by Amyloid-β42 Oligomers but not Amyloid-β40 in Cellular Membranes
(2017) J of Biol Chem 292, 1404-1413

[4] Barritt JD., Viles JH
Truncated Amyloid-β (11-40/42) from Alzheimer’s Disease Binds Copper2+ with a Femtomolar Affinity and Influences Fibre Assembly.
(2015) J of Biol Chem. 290, 27791-27802

N‐Terminally Truncated Amyloid‐β (11‐40/42) Co‐Fibrillises with its Full‐Length Counterpart, Implications for Alzheimer’s Disease
JD Barritt, ND Younan, JH Viles*
(2017) Angewandte Chemie 129, 9948–9951

[5] Matheou CJ, Younan ND, Viles JH. The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures
(2016) J Mol Biol 428, 2832-2846


BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
AgeingNeurobiologyStructural Biology
Techniques & Approaches
BiochemistryBiophysicsChemistryMicroscopy / Electrophysiology