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  1. Article ; Online: Quantitation of Tissue Amyloid via Fluorescence Spectroscopy Using Controlled Concentrations of Thioflavin-S.

    MacKeigan, Tatiana P / Morgan, Megan L / Stys, Peter K

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 11

    Abstract: Amyloids are misfolded proteins that aggregate into fibrillar structures, the accumulation of which is associated with the pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease (AD). Early, sensitive detection of these misfolded ... ...

    Abstract Amyloids are misfolded proteins that aggregate into fibrillar structures, the accumulation of which is associated with the pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease (AD). Early, sensitive detection of these misfolded aggregates is of great interest to the field, as amyloid deposition begins well before the presentation of clinical symptoms. Thioflavin-S (ThS) is a fluorescent probe commonly used to detect amyloid pathology. Protocols for ThS staining vary, but they often use high staining concentrations followed by differentiation, which causes varying levels of non-specific staining and potentially leaves more subtle amyloid deposition unidentified. In this study, we developed an optimized ThS staining protocol for the sensitive detection of β-amyloids in the widely used 5xFAD Alzheimer's mouse model. Controlled dye concentrations together with fluorescence spectroscopy and advanced analytical methods enabled not only the visualization of plaque pathology, but also the detection of subtle and widespread protein misfolding throughout the 5xFAD white matter and greater parenchyma. Together, these findings demonstrate the efficacy of a controlled ThS staining protocol and highlight the potential use of ThS for the detection of protein misfolding that precedes clinical manifestation of disease.
    MeSH term(s) Mice ; Animals ; Spectrometry, Fluorescence ; Alzheimer Disease/metabolism ; Amyloidogenic Proteins/metabolism ; Amyloid ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism ; Mice, Transgenic
    Chemical Substances Amyloidogenic Proteins ; Amyloid ; Amyloid beta-Peptides
    Language English
    Publishing date 2023-06-01
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28114483
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  2. Article ; Online: Dual-probe fluorescence spectroscopy for sensitive quantitation of Alzheimer's amyloid pathology.

    Stepanchuk, Anastasiia A / Morgan, Megan L / Joseph, Jeffrey T / Stys, Peter K

    Acta neuropathologica communications

    2022  Volume 10, Issue 1, Page(s) 153

    Abstract: Protein misfolding is a prominent pathological hallmark of neurodegenerative disorders, including Alzheimer's disease (AD). Studies have shown that the diversity of β sheet-rich protein deposits (such as amyloid β plaques and neurofibrillary tangles), ... ...

    Abstract Protein misfolding is a prominent pathological hallmark of neurodegenerative disorders, including Alzheimer's disease (AD). Studies have shown that the diversity of β sheet-rich protein deposits (such as amyloid β plaques and neurofibrillary tangles), present across different brain regions, might underlie different disease phenotypes and only certain types of aggregates might be associated with cognitive decline. Conformationally sensitive fluorescent amyloid probes have the ability to report different structures of protein aggregates by virtue of their shifting emission spectra. Here we defined the binding affinity of the fluorescent amyloid probes BSB and MCAAD to disease-relevant protein aggregates, and combined the two probes to examine formalin-fixed paraffin-embedded mouse and human brain samples. Coupled with quantitative spectral phasor analysis, the dual-probe staining approach revealed remarkable heterogeneity of protein aggregates across the samples. Distinct emission spectra were consistent with certain types of deposits present in the mouse and human brain sections. The sensitivity of this staining, imaging and analysis approach outperformed conventional immunohistochemistry with the detected spectral differences between the greater parenchyma of cognitively normal and AD cases indicating a subtle yet widespread proteopathy associated with disease. Our method offers more sensitive, objective, and quantitative examination of protein misfolding pathology using conventional tissue sections.
    MeSH term(s) Animals ; Humans ; Mice ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/pathology ; tau Proteins/metabolism ; Protein Aggregates ; Spectrometry, Fluorescence ; Plaque, Amyloid/pathology ; Amyloid/metabolism ; Brain/pathology ; Amyloidosis/pathology ; Fluorescent Dyes/metabolism
    Chemical Substances Amyloid beta-Peptides ; tau Proteins ; Protein Aggregates ; Amyloid ; Fluorescent Dyes
    Language English
    Publishing date 2022-10-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-022-01456-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Autofluorescence spectroscopy as a proxy for chronic white matter pathology.

    Morgan, Megan L / Kaushik, Deepak K / Stys, Peter K / Caprariello, Andrew V

    Multiple sclerosis (Houndmills, Basingstoke, England)

    2020  Volume 27, Issue 7, Page(s) 1046–1056

    Abstract: Background: The balance of tissue injury and repair ultimately determines outcomes of chronic neurological disorders, such as progressive multiple sclerosis (MS). However, the extent of pathology can be difficult to detect, particularly when it is ... ...

    Abstract Background: The balance of tissue injury and repair ultimately determines outcomes of chronic neurological disorders, such as progressive multiple sclerosis (MS). However, the extent of pathology can be difficult to detect, particularly when it is insidious and/or offset by tissue regeneration.
    Objectives: The objective of this research is to evaluate whether tissue autofluorescence-typically a source of contamination-provides a surrogate marker of white matter injury.
    Methods: Tissue autofluorescence in autopsied specimens both experimental and clinical was characterized by spectral confocal microscopy and correlated to severity and chronicity as determined by standard histopathology.
    Results: Months after cuprizone (CPZ)-induced demyelination, despite robust remyelination, autofluorescent deposits progressively accumulated in regions of prior pathology. Autofluorescent deposits (likely reflecting myelin debris remnants) were conspicuously localized to white matter, proportional to lesion severity, and displayed differential fluorescence over time. Strikingly, similar features were apparent also in autopsied MS tissue.
    Conclusion: Autofluorescence spectroscopy illuminates prior and ongoing white matter injury. The accumulation of autofluorescence in proportion to the extent of progressive atrophy, despite robust remyelination in the CPZ brain, provides important proof-of-concept of a phenomenon (insidious ongoing damage masked by mechanisms of tissue repair) that we hypothesize is highly relevant to the progressive phase of MS.
    MeSH term(s) Animals ; Cuprizone ; Demyelinating Diseases ; Disease Models, Animal ; Humans ; Mice ; Mice, Inbred C57BL ; Myelin Sheath ; Spectrum Analysis ; White Matter/diagnostic imaging
    Chemical Substances Cuprizone (5N16U7E0AO)
    Language English
    Publishing date 2020-08-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1290669-4
    ISSN 1477-0970 ; 1352-4585
    ISSN (online) 1477-0970
    ISSN 1352-4585
    DOI 10.1177/1352458520948221
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4428: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper.

    Morgan, Megan L / Teo, Wulin / Hernandez, Yda / Brideau, Craig / Cummins, Karen / Kuipers, Hedwich F / Stys, Peter K

    ASN neuro

    2022  Volume 14, Page(s) 17590914221126367

    Abstract: Summary statement: The demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex. ...

    Abstract Summary statement: The demyelinating effects of CPZ are not due to Cu deficiency but are instead consistent with acute toxicity of a CPZ + Cu complex.
    MeSH term(s) Animals ; Brain ; Copper/toxicity ; Cuprizone/toxicity ; Demyelinating Diseases/chemically induced ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL
    Chemical Substances Cuprizone (5N16U7E0AO) ; Copper (789U1901C5)
    Language English
    Publishing date 2022-09-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2485467-0
    ISSN 1759-0914 ; 1759-0914
    ISSN (online) 1759-0914
    ISSN 1759-0914
    DOI 10.1177/17590914221126367
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Nile Red fluorescence spectroscopy reports early physicochemical changes in myelin with high sensitivity.

    Teo, Wulin / Caprariello, Andrew V / Morgan, Megan L / Luchicchi, Antonio / Schenk, Geert J / Joseph, Jeffrey T / Geurts, Jeroen J G / Stys, Peter K

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 8

    Abstract: The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the ... ...

    Abstract The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the earliest indication of myelin injury involves changes in the composition and/or polarity of its constituent lipids, we developed a sensitive spectroscopic technique for defining the chemical polarity of myelin lipids in fixed frozen tissue sections from rodent and human. The method uses a simple staining procedure involving the lipophilic dye Nile Red, whose fluorescence spectrum varies according to the chemical polarity of the microenvironment into which the dye embeds. Nile Red spectroscopy identified histologically intact yet biochemically altered myelin in prelesioned tissues, including mouse white matter following subdemyelinating cuprizone intoxication, as well as normal-appearing white matter in multiple sclerosis brain. Nile Red spectroscopy offers a relatively simple yet highly sensitive technique for detecting subtle myelin changes.
    MeSH term(s) Aged ; Animals ; Case-Control Studies ; Cell Line ; Cuprizone/toxicity ; Demyelinating Diseases/chemically induced ; Demyelinating Diseases/pathology ; Fluorescent Dyes ; Gray Matter/chemistry ; Gray Matter/cytology ; Humans ; Lipids/chemistry ; Male ; Mice, Inbred C57BL ; Middle Aged ; Multiple Sclerosis/pathology ; Myelin Sheath/chemistry ; Oligodendroglia/chemistry ; Oligodendroglia/pathology ; Oxazines/chemistry ; Spectrometry, Fluorescence/methods ; White Matter/chemistry ; White Matter/cytology ; Mice
    Chemical Substances Fluorescent Dyes ; Lipids ; Oxazines ; Cuprizone (5N16U7E0AO) ; nile red (P476F1L81G)
    Language English
    Publishing date 2021-02-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2016897118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Biochemically altered myelin triggers autoimmune demyelination.

    Caprariello, Andrew V / Rogers, James A / Morgan, Megan L / Hoghooghi, Vahid / Plemel, Jason R / Koebel, Adam / Tsutsui, Shigeki / Dunn, Jeffrey F / Kotra, Lakshmi P / Ousman, Shalina S / Wee Yong, V / Stys, Peter K

    Proceedings of the National Academy of Sciences of the United States of America

    2018  Volume 115, Issue 21, Page(s) 5528–5533

    Abstract: Although immune attack against central nervous system (CNS) myelin is a central feature of multiple sclerosis (MS), its root cause is unresolved. In this report, we provide direct evidence that subtle biochemical modifications to brain myelin elicit ... ...

    Abstract Although immune attack against central nervous system (CNS) myelin is a central feature of multiple sclerosis (MS), its root cause is unresolved. In this report, we provide direct evidence that subtle biochemical modifications to brain myelin elicit pathological immune responses with radiological and histological properties similar to MS lesions. A subtle myelinopathy induced by abbreviated cuprizone treatment, coupled with subsequent immune stimulation, resulted in lesions of inflammatory demyelination. The degree of myelin injury dictated the resulting immune response; biochemical damage that was too limited or too extensive failed to trigger overt pathology. An inhibitor of peptidyl arginine deiminases (PADs), enzymes that alter myelin structure and correlate with MS lesion severity, mitigated pathology even when administered only during the myelin-altering phase. Moreover, cultured splenocytes were reactive against donor myelin isolates, a response that was substantially muted when splenocytes were exposed to myelin from donors treated with PAD inhibitors. By showing that a primary biochemical myelinopathy can trigger secondary pathological inflammation, "cuprizone autoimmune encephalitis" potentially reconciles conflicting theories about MS pathogenesis and provides a strong rationale for investigating myelin as a primary target for early, preventative therapy.
    MeSH term(s) Animals ; Cuprizone/toxicity ; Demyelinating Diseases/etiology ; Demyelinating Diseases/pathology ; Disease Models, Animal ; Encephalitis/chemically induced ; Encephalitis/immunology ; Encephalitis/pathology ; Hashimoto Disease/chemically induced ; Hashimoto Disease/immunology ; Hashimoto Disease/pathology ; Humans ; Hydrolases/genetics ; Hydrolases/metabolism ; Inflammation/chemically induced ; Inflammation/immunology ; Inflammation/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Monoamine Oxidase Inhibitors/toxicity ; Multiple Sclerosis/etiology ; Multiple Sclerosis/pathology ; Myelin Sheath/immunology ; Myelin Sheath/metabolism ; Myelin Sheath/pathology
    Chemical Substances Monoamine Oxidase Inhibitors ; Cuprizone (5N16U7E0AO) ; Hydrolases (EC 3.-) ; arginine deiminase (EC 3.5.3.6)
    Language English
    Publishing date 2018-05-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1721115115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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