Alzheimer’s disease and the β-amyloid peptide: Aβ conformers and mechanisms of spreading

Abstract

Alzheimer’ s disease (AD) is a progressive neurodegenerative condition characterized by an amnestic memory impairment and behavioral changes. According to the amyloid cascade hypothesis postulated by Hardy in 1992, the accumulation and subsequent aggregation of the β-amyloid protein (Aβ) is the initial trigger of the disease. Overwhelming research has recently shown that the Aβ peptide shares similarities with the prion protein - a protein that once aggregated transmits its misfolded shape onto physiological forms of the same protein and thereby becomes self-propagating. The overall objective of this doctoral dissertation was to further investigate the prion-like characteristics of the Aβ protein. Three studies were performed analyzing different aggregate conformations and the resistance of plaque polymorphism towards degradation as well as the characterization of new mouse models to study the spatiotemporal progression of protein aggregation throughout the brain. The first study analyzed the structural features of amyloid plaque cores in postmortem tissue of a heterogenous cohort of more than 40 AD patients displaying both sporadic as well as familiar forms of the disease. Evaluation of the structural plaque core features was performed using a combination of conformational sensitive amyloid dyes. The results indicate that amyloid conformations vary among patient subgroups and reveal important insight into the heterogeneity of plaque morphologies in postmortem end stage AD brain. The second study investigated the durability of plaque polymorphism in transgenic mouse brain. It emphasizes the prolonged durability of plaque polymorphism over serial transmission and the importance of the Aβ42 peptide in the propagation of strain-like morphologies. In the third study, two new mouse models overexpressing murine Aβ were characterized and their ability to study the propagation of Aβ seeds within axonally connected areas was evaluated.