| 1. |
- Ellingsen, Pal Gunnar, et al.
(författare)
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Spectral correlation analysis of Amyloid beta plaque inhomogeneity from double staining experiments
- 2013
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Ingår i: Journal of Biomedical Optics. - : Society of Photo-optical Instrumentation Engineers (SPIE). - 1083-3668 .- 1560-2281. ; 18:10
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Tidskriftsartikel (refereegranskat)abstract
- A spectral correlation algorithm for the analysis of hyperspectral fluorescence images is proposed by Ellingsen et al. [J. Biomed. Opt. 18, 020501 (2013)]. Here, it is applied to the analysis of double-stained A beta amyloid plaques being related to the Alzheimers disease (AD). Sections of APP/PS1 AD mice model brains are double stained with luminescent-conjugated oligothiophenes, known to bind to amyloid protein deposits. Hyperspectral fluorescence images of the brain sections are recorded and by applying the correlation algorithm the spectral inhomogeneity of the double-stained samples is mapped in terms of radial distribution and spectral content. To further investigate the progression of A beta amyloid plaque formation, 19 AD mice of different ages up to 23 months are characterized, enabling a statistical analysis of the plaque heterogeneity. In accordance with recent findings by Nystrom et al. [ACS Chem. Biol. 8, 1128-1133 (2013)], the spectral distribution within A beta plaques is found to vary with age throughout the lifespan of the mouse. With the new correlation algorithm, it is possible to quantify the spectral abundance of the two stains depending on the relative distance from the plaque center and mouse age. Thus, we demonstrate the use of the correlation analysis approach in double-staining experiments and how it is possible to relate these to structural/spectral changes in biological samples. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
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| 2. |
- Michno, Wojciech, 1992, et al.
(författare)
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Pyroglutamation of amyloid-βx-42 (Aβx-42) followed by Aβ1–40 deposition underlies plaque polymorphism in progressing Alzheimer's disease pathology
- 2019
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Ingår i: Journal of Biological Chemistry. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258 .- 1083-351X. ; 294:17, s. 6719-6732
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid- (A) pathology in Alzheimer's disease (AD) is characterized by the formation of polymorphic deposits comprising diffuse and cored plaques. Because diffuse plaques are predominantly observed in cognitively unaffected, amyloid-positive (CU-AP) individuals, pathogenic conversion into cored plaques appears to be critical to AD pathogenesis. Herein, we identified the distinct A species associated with amyloid polymorphism in brain tissue from individuals with sporadic AD (s-AD) and CU-AP. To this end, we interrogated A polymorphism with amyloid conformation-sensitive dyes and a novel in situ MS paradigm for chemical characterization of hyperspectrally delineated plaque morphotypes. We found that maturation of diffuse into cored plaques correlated with increased A1-40 deposition. Using spatial in situ delineation with imaging MS (IMS), we show that A1-40 aggregates at the core structure of mature plaques, whereas A1-42 localizes to diffuse amyloid aggregates. Moreover, we observed that diffuse plaques have increased pyroglutamated Ax-42 levels in s-AD but not CU-AP, suggesting an AD pathology-related, hydrophobic functionalization of diffuse plaques facilitating A1-40 deposition. Experiments in tgAPP(Swe) mice verified that, similar to what has been observed in human brain pathology, diffuse deposits display higher levels of A1-42 and that A plaque maturation over time is associated with increases in A1-40. Finally, we found that A1-40 deposition is characteristic for cerebral amyloid angiopathy deposition and maturation in both humans and mice. These results indicate that N-terminal Ax-42 pyroglutamation and A1-40 deposition are critical events in priming and maturation of pathogenic A from diffuse into cored plaques, underlying neurotoxic plaque development in AD.
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| 3. |
- Nyström, Sofie, et al.
(författare)
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Evidence for Age-Dependent in Vivo Conformational Rearrangement within A beta Amyloid Deposits
- 2013
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Ingår i: ACS Chemical Biology. - : American Chemical Society. - 1554-8929 .- 1554-8937. ; 8:6, s. 1128-1133
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Tidskriftsartikel (refereegranskat)abstract
- Deposition of aggregated A beta peptide in the brain is one of the major hallmarks of Alzheimers disease. Using a combination of two structurally different, but related, hypersensitive fluorescent amyloid markers, LCOs, reporting on separate ultrastructural elements, we show that conformational rearrangement occurs within A beta plaques of transgenic mouse models as the animals age. This important mechanistic insight should aid the design and evaluation of experiments currently using plaque load as readout.
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| 4. |
- Wang, Chao, 1986-, et al.
(författare)
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S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.
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