Abstract
Loss of memory during Alzheimer's disease (AD), a fatal neurodegenerative disorder, is associated with neuronal loss and the aggregation of amyloid proteins into neurotoxic β‐sheet enriched structures. However, the mechanism of amyloid protein aggregation is still not well understood due to many challenges when studying the endogenous amyloid structures in neurons or in brain tissue. Available methods either require chemical processing of the sample or may affect the amyloid protein structure itself. Therefore, new approaches, which allow studying molecular structures directly in neurons, are urgently needed. A novel approach is tested, based on label‐free optical photothermal infrared super‐resolution microspectroscopy, to study AD‐related amyloid protein aggregation directly in the neuron at sub‐micrometer resolution. Using this approach, amyloid protein aggregates are detected at the subcellular level, along the neurites and strikingly, in dendritic spines, which has not been possible until now. Here, a polymorphic nature of amyloid structures that exist in AD transgenic neurons is reported. Based on the findings of this work, it is suggested that structural polymorphism of amyloid proteins that occur already in neurons may trigger different mechanisms of AD progression.
Highlights
Loss of memory during Alzheimer’s disease (AD), a fatal neurodegenerative recent results with an immunotherapy clinical trial using aducadisorder, is associated with neuronal loss and the aggregation of amyloid numab targeting the β-amyloid protein proteins into neurotoxic β-sheet enriched structures
Our results suggest that different mechanisms of Aβ aggregation may exist simultaneously already in a neuron: one mechanism is the formation of β-sheet structures and another mechanism could be the formation of unordered membrane toxic β-sheet aggregates, different mechanisms of Aβ neurotoxicity might be triggered
Our data shows that optical photothermal infrared (O-PTIR), a novel label-free highly sensitive super-resolution chemical imaging approach is capable of characterizing amyloid structures present inside neurons at sub-micrometer resolution, providing an opportunity to determine molecular structures that may form in diseased neurons and drive AD progression
Summary
Loss of memory during Alzheimer’s disease (AD), a fatal neurodegenerative recent results with an immunotherapy clinical trial using aducadisorder, is associated with neuronal loss and the aggregation of amyloid numab targeting the β-amyloid protein proteins into neurotoxic β-sheet enriched structures. New approaches, which allow studying molecular structures ated during the intracellular cleavage of directly in neurons, are urgently needed. A novel approach is tested, based on label-free optical photothermal infrared super-resolution microspectroscopy, to study AD-related amyloid protein aggregation directly in the neuron at submicrometer resolution. Using this approach, amyloid protein aggregates are a receptor-like amyloid precursor protein (APP), and according to the amyloid cascade hypothesis, a gradual accumulation of monomeric Aβ in the extracellular space and within neurons may lead to Aβ detected at the subcellular level, along the neurites and strikingly, in dendritic aggregation Electron, immunois increasing rapidly at the present time in the modern world.[1] electron, confocal immunofluorescence, and super-resolution
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