MSACL 2019 EU Abstract

Pyroglutamation of Amyloid-β-42 (Aβ1-42) Followed by Aβ1-40 Deposition Underlies Plaque Polymorphism in Progressing Alzheimer’s Disease Pathology

Wojciech Michno (1), Henrik Zetterberg (1,2), Kaj Blennow (1), Jörg Hanrieder (1,2)
(1) University of Gothenburg, Sweden, (2) University College London, UK

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Jörg Hanrieder (Presenter) University of Gothenburg >> POSTER (PDF)

Presenter Bio: Jörg Hanrieder graduated with a MSc in chemistry from Leipzig University in 2005 followed by research stays at Ohio University and Adelaide University, Australia. He completed his PhD at Uppsala University, Sweden in 2010 within neurochemistry, where he worked on neuropeptide and protein profiling in neurodegenerative diseases After graduating, he joined Chalmers University, Gothenburg, Sweden as a postdoc fellow within chemical imaging. In 2015, he established his own research group as at the Institute of Neuroscience and Physiology, at the Sahlgrenska Medical School at Gothenburg University. In 2017 he was tenured as Docent/Associate Professor in Neurobiology and is currently heading a biomedical research lab at the clinical chemistry division at the Sahlgrenska University Hospital in Mölndal.

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Conflict mitigation NOT REQUIRED.

Introduction:
Amyloidogenic aggregation of beta-amyloid (Abeta) peptides into senile deposits is the major pathological hallmark of Alzheimer’s disease (AD). The exact mechanisms of AD remain unclear though plaque pathology has been identified as critical. However, Abeta plaques have been found in cognitively unaffected patients that are amyloid positve (CUAP). However, Aβ plaques present in CUAP are mostly diffuse, while plaques in AD brain are mostly mature/compact. Diffuse plaques can therefore represent an immature non-toxic state of mature compact amyloid plaques.

Objective:
As the factors that promote neurotoxic plaque formation are still unknown, changes in Abeta peptide truncation have been implicated with proteopathic mechanisms in AD.
Therefore, a chemical imaging that allows the efficient discrimination of structural and molecular plaque architecture is of essential interest to resolve Aβ plaque pathology in AD.

Methods;
To delineate plaque pathology a novel, multimodal chemical imaging paradigm based on MALDI imaging mass spectrometry in combination with fluorescent probes and immunohistochemistry was developed.Here MALDI IMS on brain tissue was combined with fluorescent amyloid staining using luminescent conjugated oligothiophene probes that recognize structural characteristics of Aβ aggregation dynamics. This technology was applied to probe amyloid polymorphism in human post mortem brain from AD and CUAP individuals as well as in transgenic AD mice.

Results:
The data on in human and mouse tissue show both a significant increase of Aβ1-40 in senile, neurotoxic plaques as compared to plaques of diffuse, pre-amyloid morphology, where no Aβ1-40 was observed both in human AD as well as CUAP. Additional data in mice show that this increase in Aβ1-40 was associated with plaque maturation over time, where both senile plaques and cerebrovascular deposits at 18 months contained higher Aβ1-40/1-42 levels than at 12 months. Further, pyroglutamation of Abeta 3-42 (3pE-42) was found increased only in AD plaques.

Discussion and Conclusion:
A proportionally higher Aβ1-42 content appears therefore to be characteristic for pre-mature deposits and 3pE truncation specific to AD pathology. This suggests diffuse plaques to be precursors of senile plaques and that maturation into senile plaques is associated with AD.pathogenesis involving hydrophobic functionalization through N-terminal pyroglutamation of Abeta 1-42 followed by deposition of more soluble Abeta 1-40.
Taken together, the here presented hyperspectral chemical imaging paradigm of individual, chemically and structurally delineated Aβ deposits provides insight in the chemical aspects underlying evolving plaque pathology in AD that is not facilitated by other biochemical techniques.