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- Dreos, Ambra, 1987, et al.
(författare)
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Investigating New Applications of a Photoswitchable Fluorescent Norbornadiene as a Multifunctional Probe for Delineation of Amyloid Plaque Polymorphism.
- 2023
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Ingår i: ACS sensors. - : American Chemical Society (ACS). - 2379-3694. ; 8:4, s. 1500-1509
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta (Aβ) plaques are a major pathological hallmark of Alzheimer's disease (AD) and constitute of structurally heterogenic entities (polymorphs) that have been implicated in the phenotypic heterogeneity of AD pathology and pathogenesis. Understanding amyloid aggregation has been a critical limiting factor to gain understanding of AD pathogenesis, ultimately reflected in that the underlying mechanism remains elusive. We identified a fluorescent probe in the form of a turn-off photoswitchable norbornadiene derivative (NBD1) with several microenvironment-sensitive properties that make it relevant for applications within advanced fluorescence imaging, for example, multifunctional imaging. We explored the application of NBD1 for in situ delineation of structurally heterogenic Aβ plaques in transgenic AD mouse models. NBD1 plaque imaging shows characteristic broader emission bands in the periphery and more narrow emission bands in the dense cores of mature cored plaques. Further, we demonstrate in situ photoisomerization of NBD1 to quadricyclane and thermal recovery in single plaques, which is relevant for applications within both functional and super-resolution imaging. This is the first time a norbornadiene photoswitch has been used as a probe for fluorescence imaging of Aβ plaque pathology in situ and that its spectroscopic and switching properties have been studied within the specific environment of senile Aβ plaques. These findings open the way toward new applications of NBD-based photoswitchable fluorescent probes for super-resolution or dual-color imaging and multifunctional microscopy of amyloid plaque heterogeneity. This could allow to visualize Aβ plaques with resolution beyond the diffraction limit, label different plaque types, and gain insights into their physicochemical composition.
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| 2. |
- Ge, Junyue, 1993, et al.
(författare)
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Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer?s Disease Models
- 2023
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 95:10, s. 4692-4702
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Tidskriftsartikel (refereegranskat)abstract
- Beta-amyloid (AP) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking AP to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of AP aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid-AP correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid-and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid and AP patterns, including AP 1-40 and AP 1-42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with AP peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with AP core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous AP deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.
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| 3. |
- Koutarapu, Srinivas, et al.
(författare)
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Correlative Chemical Imaging Identifies Amyloid Peptide Signatures of Neuritic Plaques and Dystrophy in Human Sporadic Alzheimer's Disease.
- 2023
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Ingår i: Brain connectivity. - : Mary Ann Liebert Inc. - 2158-0014 .- 2158-0022. ; 15:5, s. 297-306
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Alzheimer's disease (AD) is the most common neurodegenerative disease. The predominantly sporadic form of AD is age-related, but the underlying pathogenic mechanisms remain not fully understood. Current efforts to combat the disease focus on the main pathological hallmarks, in particular beta-amyloid (Aβ) plaque pathology. According to the amyloid cascade hypothesis, Aβ is the critical early initiator of AD pathogenesis. Plaque pathology is very heterogeneous, where a subset of plaques, neuritic plaques (NPs), are considered most neurotoxic rendering their in-depth characterization essential to understand Aβ pathogenicity. Methods: To delineate the chemical traits specific to NP types, we investigated senile Aβ pathology in the postmortem, human sporadic AD brain using advanced correlative biochemical imaging based on immunofluorescence (IF) microscopy and mass spectrometry imaging (MSI). Results: Immunostaining-guided MSI identified distinct Aβ signatures of NPs characterized by increased Aβ1-42(ox) and Aβ2-42. Moreover, correlation with a marker of dystrophy (reticulon 3 [RTN3]) identified key Aβ species that both delineate NPs and display association with neuritic dystrophy. Conclusion: Together, these correlative imaging data shed light on the complex biochemical architecture of NPs and associated dystrophic neurites. These in turn are obvious targets for disease-modifying treatment strategies, as well as novel biomarkers of Aβ pathogenicity.
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