Following spatial Aβ aggregation dynamics in evolving Alzheimer's disease pathology by imaging stable isotope labeling kinetics

beta-Amyloid (A beta) plaque formation is the major pathological hallmark of Alzheimer's disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how A beta pathology is initiated and where and when distinct A beta species aggregate. Here, we used metabolic isotope labeling in APP(NL-G-F) knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of A beta deposition through ongoing plaque development. This allowed visualizing A beta aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential A beta peptide deposition. Specifically, A beta 1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of A beta 1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

Automated summary

The study used metabolic isotope labeling and mass spectrometry imaging techniques to monitor the earliest seeds of Aβ plaque formation and revealed the aggregation dynamics of different Aβ species within plaques. It was found that the formation of structurally distinct plaques is associated with differential Aβ peptide deposition, with Aβ 1-42 forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ 1-38.