Amyloid β peptide: from monomer solubility to fibril structure

• Alzheimer´s disease (AD) is the most common human neuro-degenerative disease characterized by the formation of cerebral plaques. Several are the amyloid-beta (Aβ) variants found in the brain of healthy individuals. Among them, the Aβ40 variant is predominantly found in the cerebrospinal fluid while the Aβ42 variant appears as fibrillar aggregates in the brain of AD patients. In vitro studies confirm that Aβ42 is more aggregation-prone than Aβ40; however, it is difficult to determine the solubility in a complex environment such as the human brain.The propensity of Aβ fibrils to catalyze the formation of new aggregates via the interaction of soluble monomers with the fibril surface drives the attention towards Aβ fibril structures; however, a detailed model for these structures is lacking. This thesis presents the development of a bottom-up protocol for the in vitro detection of the solubility of Aβ40 peptide in pure buffer conditions, i.e. the concentration in solution at equilibrium. It is shown that by working with peptides that are recombinantly expressed in E. coli cells and purified to high homogeneity, the aggregation propensity of Aβ40 peptide canbe measured in vitro via systematic and reproducible solubility studies.The second part of the thesis focuses on the investigation of the structures formed at the end state of fibril formation. A model calculation is here proposed for the determination of Aβ fibril shape, cross-section dimensions and most importantly, the number of filaments based on small angle scattering data. The relation between Aβ40 and 42 variants’ solubility concentrations and the high resolution structures of Aβ fibrils can help design experiments to elucidate thefactors that cause AD and provide a basis for the development of more effective treatments.

Ämnesord

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Nyckelord

Alzheimer´s disease

Aβ solubility

small angle scattering

number of filaments

Aβ40, Aβ42 and Aβ42 S26Q , fibril structure

Publikations- och innehållstyp

dok (ämneskategori)

vet (ämneskategori)