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- Klingstedt, Therése, et al.
(författare)
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Thiophene-Based Ligands for Specific Assignment of Distinct Aβ Pathologies in Alzheimer's Disease
- 2024
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Ingår i: ACS CHEMICAL NEUROSCIENCE. - : AMER CHEMICAL SOC. - 1948-7193. ; 15:7, s. 1581-1595
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated species of amyloid-beta (A beta) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different A beta deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of A beta deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the PSEN1 A431E mutation. When binding to A beta deposits, the ligands could easily be distinguished for their different fluorescence, and distinct staining patterns were revealed for these two types of AD. In sporadic AD, HS-276 consistently labeled all immunopositive A beta plaques, whereas LL-1 mainly stained cored and neuritic A beta deposits. In the PSEN1 A431E cases, each ligand was binding to specific types of A beta plaques. The ligand-labeled A beta deposits were localized in distinct cortical layers, and a laminar staining pattern could be seen. Biochemical characterization of the A beta aggregates in the individual layers also showed that the variation of ligand binding properties was associated with certain A beta peptide signatures. For the PSEN1 A431E cases, it was concluded that LL-1 was binding to cotton wool plaques, whereas HS-276 mainly stained diffuse A beta deposits. Overall, our findings showed that a combination of ligands was essential to identify distinct aggregated A beta species associated with different forms of AD.
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| 2. |
- Michno, Wojciech, 1992, et al.
(författare)
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Spatial Neurolipidomics at the Single Amyloid-β Plaque Level in Postmortem Human Alzheimer's Disease Brain
- 2024
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Ingår i: ACS CHEMICAL NEUROSCIENCE. - 1948-7193. ; 15:4, s. 877-888
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Tidskriftsartikel (refereegranskat)abstract
- Lipid dysregulations have been critically implicated in Alzheimer's disease (AD) pathology. Chemical analysis of amyloid-beta (A beta) plaque pathology in transgenic AD mouse models has demonstrated alterations in the microenvironment in the direct proximity of A beta plaque pathology. In mouse studies, differences in lipid patterns linked to structural polymorphism among A beta pathology, such as diffuse, immature, and mature fibrillary aggregates, have also been reported. To date, no comprehensive analysis of neuronal lipid microenvironment changes in human AD tissue has been performed. Here, for the first time, we leverage matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) through a high-speed and spatial resolution commercial time-of-light instrument, as well as a high-mass-resolution in-house-developed orbitrap system to characterize the lipid microenvironment in postmortem human brain tissue from AD patients carrying Presenilin 1 mutations (PSEN1) that lead to familial forms of AD (fAD). Interrogation of the spatially resolved MSI data on a single A beta plaque allowed us to verify nearly 40 sphingolipid and phospholipid species from diverse subclasses being enriched and depleted, in relation to the A beta deposits. This included monosialo-gangliosides (GM), ceramide monohexosides (HexCer), ceramide-1-phosphates (CerP), ceramide phosphoethanolamine conjugates (PE-Cer), sulfatides (ST), as well as phosphatidylinositols (PI), phosphatidylethanolamines (PE), and phosphatidic acid (PA) species (including Lyso-forms). Indeed, many of the sphingolipid species overlap with the species previously seen in transgenic AD mouse models. Interestingly, in comparison to the animal studies, we observed an increased level of localization of PE and PI species containing arachidonic acid (AA). These findings are highly relevant, demonstrating for the first time A beta plaque pathology-related alteration in the lipid microenvironment in humans. They provide a basis for the development of potential lipid biomarkers for AD characterization and insight into human-specific molecular pathway alterations.
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