Chemical Imaging of Evolving Amyloid Plaque Pathology and Associated Aβ Peptide Aggregation in a Transgenic Mouse Model of Alzheimer’s Disease

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid beta (Abeta) plaques. While Abeta has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Abeta plaque pathology manifests itself upon aggregation of distinct Abeta 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 Abeta aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Abeta 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 Abeta 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 Abeta (Abeta1-42). Plaque maturation was found to be characterized by a relative increase in deposition of Abeta1-40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C-terminally truncated Abeta species (Abeta1-38 and Abeta1-39) exhibited a similar aggregation pattern as Abeta1-40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Abeta1-42; a process that is followed by plaque maturation upon deposition of Abeta1-40 as well as deposition of other C-terminally modified Abeta species.