Following spatial Aβ aggregation dynamics in evolving Alzheimer's disease pathology by imaging stable isotope labeling kinetics

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer's disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ...

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Bibliographic Details
Published in:Science advances 2021-06, Vol.7 (25)
Main Authors: Michno, Wojciech, Stringer, Katie M, Enzlein, Thomas, Passarelli, Melissa K, Escrig, Stephane, Vitanova, Karina, Wood, Jack, Blennow, Kaj, Zetterberg, Henrik, Meibom, Anders, Hopf, Carsten, Edwards, Frances A, Hanrieder, Jörg
Format: Article
Language:English
Subjects:
Aggregation dynamics
Alzheimer Disease - metabolism
Alzheimer's disease
Alzheimer's disease pathologies
Amyloid beta-Peptides - metabolism
Animals
Brain
Brain - metabolism
Core structure
Deposition
Disease Models, Animal
Glycoproteins
Image processing
Isotope Labeling
Isotopes
Kinetics
Mammals
Mass spectrometry
Mass-spectrometry imaging
Mice
Mice, Transgenic
Neurodegenerative diseases
Neuroscience
Neurosciences
Neurovetenskaper
Pathology
Plaque development
Plaque, Amyloid - pathology
Research Methods
SciAdv r-articles
Stable-isotope labeling
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Summary:β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer's disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abg4855