GM1 locates to mature amyloid structures implicating a prominent role for glycolipid-protein interactions in Alzheimer pathology
Journal article, 2019

While the molecular mechanisms underlying Alzheimer's disease (AD) remain largely unknown, abnormal accumulation and deposition of beta amyloid (AD) peptides into plaques has been proposed as a critical pathological process driving disease progression. Over the last years, neuronal lipid species have been implicated in biological mechanisms underlying amyloid plaque pathology. While these processes comprise genetic features along with lipid signaling as well as direct chemical interaction of lipid species with A beta mono- and oligomers, more efforts are needed to spatially delineate the exact lipid-A beta plaque interactions in the brain. Chemical imaging using mass spectrometry (MS) allows to probe the spatial distribution of lipids and peptides in complex biological tissues comprehensively and at high molecular specificity. As different imaging mass spectrometry (IMS) modalities provide comprehensive molecular and spatial information, we here describe a multimodal ToF-SIMS- and MALDI-based IMS strategy for probing lipid and A beta peptide changes in a transgenic mouse model of AD (tgAPP(ArcSwe)). Both techniques identified a general AD-associated depletion of cortical sulfatides, while multimodal MALDI IMS revealed plaque specific lipid as well as A beta peptide isoforms. In addition, MALDI IMS analysis revealed chemical features associated with morphological heterogeneity of individual A beta deposits. Here, an altered GM1 to GM2/GM3 ganglioside metabolism was observed in the diffuse periphery of plaques but not in the core region. This was accompanied by an enrichment of A beta 1-40arc peptide at the core of these deposits. Finally, a localization of arachidonic acid (AA) conjugated phosphatidylinositols (PI) and their corresponding degradation product, lysophosphatidylinositols (LPI) to the periphery of A beta plaques was observed, indicating site specific macrophage activation and ganglioside processing.

Author

Wojciech Michno

University of Gothenburg

Patrick M. Wehrli

University of Gothenburg

Henrik Zetterberg

University of Gothenburg

Kaj Blennow

University of Gothenburg

Jörg Hanrieder

University of Gothenburg

Chalmers, Chemistry and Chemical Engineering, Chemistry and Biochemistry, Analytical Chemistry

Biochimica et Biophysica Acta - Proteins and Proteomics

1570-9639 (ISSN)

Vol. 1867 5 458-467

Subject Categories

Pharmaceutical Sciences

Biochemistry and Molecular Biology

Biophysics

DOI

10.1016/j.bbapap.2018.09.010

PubMed

30273679

More information

Latest update

8/19/2019