β-Amyloid (Aβ) 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 Aβ pathology is initiated and where and when distinct Aβ 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 Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

β-淀粉样蛋白 (Aβ) 斑块的形成是阿尔茨海默病 (AD) 的主要病理标志，并且构成潜在的关键早期诱导剂，驱动 AD 发病机制，因为它比其他病理事件和认知症状早了几十年。因此，了解 Aβ 病理学是如何引发的以及不同 Aβ 物种聚集的地点和时间至关重要。在这里，我们在APP ^NL-GF中使用了代谢同位素标记敲入小鼠与质谱成像一起通过正在进行的斑块发育监测 Aβ 沉积的最早种子。这允许在不同大脑区域的单个斑块内可视化 Aβ 聚集动态。我们表明，结构上不同的斑块的形成与不同的 Aβ 肽沉积有关。具体而言，Aβ1-42 正在形成初始核心结构，随后是径向向外生长以及 Aβ1-38 的晚期分泌和沉积。这些数据详细描述了以前所未有的规模诱发淀粉样蛋白病理的最早事件。