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Tracking peripherally administered Amyloid-beta by stable isotope labeling-based proteomics

ABSTRACT: Findings of early cerebral Amyloid-beta deposition in mice after peripheral injection of Amyloid-beta containing brain extracts, and humans following cadaveric human growth hormone treatment raised concerns that Amyloid-beta aggregates and possibly Alzheimer disease (AD) may be transmissible between individuals. Yet, proof that Amyloid-beta actually reaches the brain from the peripheral injection site is lacking. Here, we used a proteomic approach combining stable isotope labeling of mammals and untargeted and targeted mass spectrometry. Specifically, we generated 13C-isotope labeled brain extracts from mice expressing human Amyloid-beta and track 13C-Lys-labeled Amyloid-beta after intraperitoneal administration into young Amyloid betaPP transgenic mice. We detected injected Amyloid-beta in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13C-Lys-labeled Amyloid-beta was not detectable in the brain whereas the mice incorporated 13C-Lys from the donor brain extracts into endogenous Amyloid-beta. Using a highly sensitive and specific proteomic approach, we demonstrated that Amyloid-beta does not reach the brain from the periphery. Our study argues against potential transmissibility of AD while opening new avenues to uncover mechanisms of pathophysiological protein deposition. Please note that corresponding MRM data for this project have been submitted elsewhere.

INSTRUMENT(S): MALDI Synapt G2-S HDMS, Exactive Plus

ORGANISM(S): Mus Musculus

SUBMITTER: Maciej Lalowski Mirjam Brackhan Jens Pahnke

PROVIDER: MSV000089339 | MassIVE | Fri Apr 29 11:34:00 BST 2022

SECONDARY ACCESSION(S): PXD033566

REPOSITORIES: MassIVE

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Tracking peripherally administered Amyloid-beta by stable isotope labeling-based proteomics

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