Abstract
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.
Highlights
The amyloid hypothesis places amyloid-β protein (Aβ) as a critical trigger of Alzheimer’s disease (AD)[1]
Neurons were derived from the brains of mice that lack functional amyloid precursor protein (APP-KO)[22] and do not express Aβ
Using Nanoscopium nanoprobe, we examined the elemental distribution in intact APP knockout (APP-KO) neurons and APP-KO neurons treated with Aβ (Fig. 3a)
Summary
The amyloid hypothesis places amyloid-β protein (Aβ) as a critical trigger of Alzheimer’s disease (AD)[1]. Failures of clinical trials targeting Aβ proteins indicate that the mechanisms of AD-related neurodegeneration are more complex[2,3]. Dissecting molecular mechanisms involving metal ions and structural changes of amyloid proteins in cells or tissues is a very challenging task since protein structures and metal ion concentrations can be affected by chemical processing. Sensitive label-free imaging methods are urgently required to address protein structure and elemental distribution in cells. Infrared (IR) microscopy and X-ray fluorescence spectroscopy (XRF) have been combined to study brain tissues[7] and brain cells[15]. IR light limits traditional IR microscopy to particles >∼3 μm, which provides less relevance for resolving structures at the subcellular level
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