Following spatial A beta 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.