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

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 Ab constitute 20% of plaque load. Surprisingly very little is known about these truncated forms of Ab. 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 Ab, 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]

Viles, J. H. Metal ions and amyloid fiber formation in neurodegenerative diseases. Copper, zinc and iron in Alzheimer’s, Parkinson’s and prion diseases. (2012) Coord. Chem. Rev. 256, 2271-2284 

[3]

Matheou, C. J.; Younan, N. D.; Viles, J. H. Cu2+ accentuates distinct misfolding of Abeta(1-40) and Abeta(1-42) peptides, and potentiates membrane disruption. (2015) Biochem J. 466, 233-242 

[4]

Barritt J.D., Viles J.H. 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

[5]

Matheou C. J., Younan N.D., Viles J.H. 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 in press


Biological Areas:

Neurobiology
Structural Biology

BBSRC Area:

Molecules, cells and industrial biotechnology