BookR: School of Health Core Facilities Booking

ß-Amyloid (Aß) 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 Aß pathology is initiated and where and when distinct Aß 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 Aß deposition through ongoing plaque development. This allowed visualizing Aß aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aß peptide deposition. Specifically, Aß1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aß1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.