Protein misfolding and aggregation are hallmarks of neurodegenerative diseases such as Alzheimer’s disease (AD). In AD, the accumulation and aggregation of tau and the amyloid-beta peptide Aβ₁₋₄₂ precedes the onset of AD symptoms. Modelling the aggregation of Aβ is technically very challenging in vivo due to its size of only 42 aa. Here, we employed sub-stoichiometric labelling of Aβ₁₋₄₂ in C. elegans to enable tracking of the peptide in vivo, combined with the “native” aggregation of unlabeled Aβ₁₋₄₂. Expression of Aβ₁₋₄₂ leads to severe physiological defects, neuronal dysfunction and neurodegeneration. Moreover, we can demonstrate spreading of neuronal Aβ to other tissues. Fluorescence lifetime imaging microscopy enabled a quantification of the formation of amyloid fibrils with ageing and revealed a heterogenic yet specific pattern of aggregation. Notably, we found that Aβ aggregation starts in a subset of neurons of the anterior head ganglion, the six IL2 neurons. We further demonstrate that cell-specific, RNAi-mediated depletion of Aβ in these IL2 neurons systemically delays Aβ aggregation and pathology.

蛋白质错误折叠和聚集是阿尔茨海默病 (AD) 等神经退行性疾病的标志。在 AD 中，tau 和淀粉样蛋白-β 肽 Aβ _1-42的积累和聚集先于 AD 症状的出现。由于 Aβ的大小只有 42 个氨基酸，因此在体内模拟 Aβ 的聚集在技术上非常具有挑战性。在这里，我们在秀丽隐杆线虫中采用亚化学计量标记 Aβ _1-42以实现体内肽的跟踪，结合未标记的 Aβ _1-42的“天然”聚集。Aβ _{1−42 的}表达导致严重的生理缺陷、神经元功能障碍和神经变性。此外，我们可以证明神经元 Aβ 扩散到其他组织。荧光寿命成像显微镜能够量化淀粉样原纤维随衰老的形成，并揭示了异质但特定的聚集模式。值得注意的是，我们发现 Aβ 聚集始于前头神经节的一部分神经元，即六个 IL2 神经元。我们进一步证明，这些 IL2 神经元中细胞特异性的、RNAi 介导的 Aβ 消耗系统地延迟了 Aβ 聚集和病理。