Podium Presentation in Room 4 on Thursday at 13:55 (Chair: Christopher Anderton / Wojciech Michno)
Authors: Wojciech Michno (1,2), Katie Stringer (1,2), Frances A. Edwards (2), and Jörg Hanrieder (1,3)
Characterizing the fate of various amyloid fibrillary structures in evolving Aβ pathology, is of key importance for our understanding of nerve cell death, clinical symptoms, and neurodegenerative progression in Alzheimer’s disease (AD) pathology. This is partly because in humans we can only look in detail after death and in mice we can only see a particular point in time without any longitudinal information on the fate of individually formed deposits.
We here report a novel approach, iSILK, based on metabolic labelling of proteins with stable isotopes together with ultrahigh resolution imaging for studying amyloid plaque formation dynamics in novel knock-in mouse models of AD.
Imaging of stable isotope labelling kinetics (iSILK) was performed in recently developed APP NL-G-F knock-in mouse model of AD. This to monitor the earliest seeds of Aβ deposition through ongoing plaque development and track the deposition of Aβ that is produced later in relation to already deposited plaques. For this we fed mice a diet containing a stable isotope (15N) just prior to plaque onset (PNW12) until plaque pathology was prominently manifested (PNW16). We analyzed the stable isotope enrichment in brain tissue and plaques in these mice using multimodal chemical imaging, including scanning transmission electron microscopy (STEM) nanoscale secondary ion mass spectrometry (nanoSIMS), matrix assisted laser desorption mass spectrometry (MALDI-IMS) and fluorescent structural amyloid staining (Hyperspectral LSM).
The data reveal early formation of plaques consisting primarily of Aβ1-42 in cortical areas followed by later deposition within the hippocampus. NanoSIMS reveal that these plaques form first a core structure consisting of highly abundant, soluble Aβ1-42 secreted prior to plaque deposition. In addition, these plaques form radiating diffuse fibers that evolve at a later time from the core seed. Further, other C-terminal Aβ species, including Aβ1-38 were found to be secreted at a later time during evolving plaque pathology, and were processed prior to deposition to pre-exiting Aβ1-42 containing plaque structures.
These data bring considerable novel information about the deposition mechanism of Aβ. In detail, our data show that plaque pathology is seeded by Aβ1-42, forming distinct amyloid structures that evolve into plaques. Further these data show us that the cortex is the first site of plaque deposition, something that is well in line with other mouse models. Further, we show that C-terminal Aβ processing is occurring prior to deposition and not associated with plaque specific mechanisms.
Taken together these results provide significant novel insight for understanding the earliest stages of Alzheimer’s disease and the ongoing progressive changes in amyloidosis.
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