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Shedding Light on the Molecular Pathology of Amyloid Plaques in Transgenic Alzheimer's Disease Mice Using Multimodal MALDI Imaging Mass Spectrometry

Artikel i vetenskaplig tidskrift
Författare Ibrahim Kaya
Henrik Zetterberg
Kaj Blennow
Jörg Hanrieder
Publicerad i ACS Chemical Neuroscience
Volym 9
Nummer/häfte 7
Sidor 1802-1817
ISSN 1948-7193
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Institutionen för kemi och molekylärbiologi
Sidor 1802-1817
Språk en
Länkar dx.doi.org/10.1021/acschemneuro.8b0...
Ämnesord Alzheime disease, MALDI imaging mass spectrometry, multivariate image analysis, amyloid plaque, high-spatial-resolution, alkyl-dihydroxyacetonephosphate-synthase, beta-peptide, lysophosphatidic acid, precursor protein, mouse model, a-beta, apolipoprotein-e, oxidative stress, neutral sphingomyelinase, Biochemistry & Molecular Biology, Pharmacology & Pharmacy, Neurosciences, & Neurology
Ämneskategorier Farmakologi, Biokemi och molekylärbiologi, Neurovetenskaper

Sammanfattning

Senile plaques formed by aggregated amyloid beta peptides are one of the major pathological hallmarks of Alzheimers disease (AD) which have been suggested to be the primary influence triggering the AD pathogenesis and the rest of the disease process. However, neurotoxic A beta aggregation and progression are associated with a wide range of enigmatic biochemical, biophysical and genetic processes. MALDI imaging mass spectrometry (IMS) is a label-free method to elucidate the spatial distribution patterns of intact molecules in biological tissue sections. In this communication, we utilized multimodal MALDI-IMS analysis on 18 month old transgenic AD mice (tgArcSwe) brain tissue sections to enhance molecular information correlated to individual amyloid aggregates on the very same tissue section. Dual polarity MALDI-IMS analysis of lipids on the same pixel points revealed high throughput lipid molecular information including sphingolipids, phospholipids, and lysophospholipids which can be correlated to the ion images of individual amyloid beta peptide isoforms at high spatial resolutions (10 mu m). Further, multivariate image analysis was applied in order to probe the multimodal MALDI-IMS data in an unbiased way which verified the correlative accumulations of lipid species with dual polarity and A beta peptides. This was followed by the lipid fragmentation obtained directly on plaque aggregates at higher laser pulse energies which provided tandem MS information useful for structural elucidation of several lipid species. Majority of the amyloid plaque-associated alterations of lipid species are for the first time reported here. The significance of this technique is that it allows correlating the biological discussion of all detected plaque-associated molecules to the very same individual amyloid plaques which can give novel insights into the molecular pathology of even a single amyloid plaque microenvironment in a specific brain region. Therefore, this allowed us to interpret the possible roles of lipids and amyloid peptides in amyloid plaque-associated pathological events such as focal demyelination, autophagic/lysosomal dysfunction, astrogliosis, inflammation, oxidative stress, and cell death.

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