Alzheimer’s disease (AD) is the most common cause of dementia, costing about 1% of the global economy. Failures of clinical trials targeting amyloid-β protein (Aβ), a key trigger of AD, have been explained by drug inefficiency regardless of the mechanisms of amyloid neurotoxicity, which are very difficult to address by available technologies. Here, we combine two imaging modalities that stand at opposite ends of the electromagnetic spectrum, and therefore, can be used as complementary tools to assess structural and chemical information directly in a single neuron. Combining label-free super-resolution microspectroscopy for sub-cellular imaging based on novel optical photothermal infrared (O-PTIR) and synchrotron-based X-ray fluorescence (S-XRF) nano-imaging techniques, we capture elemental distribution and fibrillary forms of amyloid-β proteins in the same neurons at an unprecedented resolution. Our results reveal that in primary AD-like neurons, iron clusters co-localize with elevated amyloid β-sheet structures and oxidized lipids. Overall, our O-PTIR/S-XRF results motivate using high-resolution multimodal microspectroscopic approaches to understand the role of molecular structures and trace elements within a single neuronal cell.

阿尔茨海默病 (AD) 是痴呆症的最常见原因，约占全球经济的 1%。以淀粉样蛋白 β 蛋白 (Aβ) 为目标的临床试验失败，这是 AD 的关键触发因素，其原因是药物效率低下，而不管淀粉样蛋白神经毒性的机制如何，现有技术很难解决这些问题。在这里，我们结合了位于电磁波谱两端的两种成像模式，因此，可以用作补充工具，直接在单个神经元中评估结构和化学信息。结合基于新型光学光热红外 (O-PTIR) 和同步加速器 X 射线荧光 (S-XRF) 纳米成像技术的亚细胞成像无标记超分辨率显微光谱，我们以前所未有的分辨率捕获相同神经元中淀粉样β蛋白的元素分布和纤维形式。我们的结果表明，在原代 AD 样神经元中，铁簇与升高的淀粉样蛋白 β 片层结构和氧化脂质共定位。总体而言，我们的 O-PTIR/S-XRF 结果促使使用高分辨率多模态显微光谱方法来了解分子结构和微量元素在单个神经元细胞中的作用。