Chemical imaging of evolving amyloid plaque pathology and associated Aß peptide aggregation in a transgenic mouse model of Alzheimer's disease.

ABSTRACT

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid ß (Aß) plaques. While Aß has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Aß plaque pathology manifests itself upon aggregation of distinct Aß peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the Aß aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Aß species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix-assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality - matrix-assisted laser desorption/ionization imaging mass spectrometry - that allows for delineating Aß aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid-long Aß (Aß1-42). Plaque maturation was found to be characterized by a relative increase in deposition of Aß1-40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C-terminally truncated Aß species (Aß1-38 and Aß1-39) exhibited a similar aggregation pattern as Aß1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Aß1-42; a process that is followed by plaque maturation upon deposition of Aß1-40 as well as deposition of other C-terminally modified Aß species.