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  • 1
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    Online Resource
    Analysis of Cerebral Small Vessel Changes in AD Model Mice
    MDPI AG ; 2022
    In:  Biomedicines Vol. 11, No. 1 ( 2022-12-25), p. 50-
    Details
    In: Biomedicines, MDPI AG, Vol. 11, No. 1 ( 2022-12-25), p. 50-
    Abstract: Amyloid β (Aβ) peptide is deposited in the brains of sporadic Alzheimer’s disease (AD) due to impaired vessel-dependent clearance. To understand the mechanisms, we investigated time-dependent cerebrovascular changes in AD model mice. Cerebrovascular and other pathological changes were analyzed in AD model mice (J20 strain) aging from 2 to 9 months by immunostaining. At 2 months, Aβ was only intraneuronal, whereas vessels were positive from 3 months in J20 mice. Compared to wild-type (WT), vessel density was increased at 2 months but decreased at 9 months in J20 mice, claudin-5 levels were decreased, and vascular endothelial growth factor (VEGF) levels were increased in the cortex and hippocampus of J20 mice brain at all time points. Albumin extravasation was evident from 3 months in J20 brains. Collagen 4 was increased at 2 and 3 months. Aquaporin 4 was spread beyond the vessels starting from 3 months in J20, which was restricted around the vessel in wild-type mice. In conclusion, the study showed that an early decrease in claudin-5 was associated with VEGF expression, indicating dysfunction of the blood–brain barrier. Decreased claudin-5 might cause the leakage of blood constituents into the parenchyma that alters astrocyte polarity and its functions.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines11010050
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720867-9
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  • 2
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    Aggregation of Cystatin C Changes Its Inhibitory Functions on Protease Activities and Amyloid β Fibril Formation
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 18 ( 2021-09-07), p. 9682-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 18 ( 2021-09-07), p. 9682-
    Abstract: Cystatin C (CST3) is an endogenous cysteine protease inhibitor, which is implicated in cerebral amyloid angiopathy (CAA). In CAA, CST3 is found to be aggregated. The purpose of this study is to investigate whether this aggregation could alter the activity of the protein relevant to the molecular pathology of CAA. A system of CST3 protein aggregation was established, and the aggregated protein was characterized. The results showed that CST3 aggregated both at 80 °C without agitation, and at 37 °C with agitation in a time-dependent manner. However, the levels of aggregation were high and appeared earlier at 80 °C. Dot-blot immunoassay for oligomers revealed that CST3 could make oligomeric aggregates at the 37 °C condition. Electron microscopy showed that CST3 could make short fibrillary aggregates at 37 °C. Cathepsin B activity assay demonstrated that aggregated CST3 inhibited the enzyme activity less efficiently at pH 5.5. At 7.4 pH, it lost the inhibitory properties almost completely. In addition, aggregated CST3 did not inhibit Aβ1-40 fibril formation, rather, it slightly increased it. CST3 immunocytochemistry showed that the protein was positive both in monomeric and aggregated CST3-treated neuronal culture. However, His6 immunocytochemistry revealed that the internalization of exogenous recombinant CST3 by an astrocytoma cell culture was higher when the protein was aggregated compared to its monomeric form. Finally, MTT cell viability assay showed that the aggregated form of CST3 was more toxic than the monomeric form. Thus, our results suggest that aggregation may result in a loss-of-function phenotype of CST3, which is toxic and responsible for cellular degeneration.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22189682
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
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  • 3
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    A Cationic Gallium Phthalocyanine Inhibits Amyloid β Peptide Fibril Formation
    Bentham Science Publishers Ltd. ; 2020
    In:  Current Alzheimer Research Vol. 17, No. 7 ( 2020-11-16), p. 589-600
    Details
    In: Current Alzheimer Research, Bentham Science Publishers Ltd., Vol. 17, No. 7 ( 2020-11-16), p. 589-600
    Abstract: Amyloid β (Aβ) peptide deposition is considered as the main cause of Alzheimer’s disease (AD). Previously, we have shown that a Zn containing neutral phthalocyanine (Zn-Pc) inhibits Aβ fibril formation. Objective: The objective of this study is to investigate the effects of a cationic gallium containing Pc (GaCl-Pc) on Aβ fibril formation process. Methods and Results: Aβ fibril formation was induced by incubating synthetic Aβ peptides in a fibril forming buffer, and the amount of fibril was evaluated by ThT fluorescence assay. GaCl-Pc dosedependently inhibited both Aβ1-40 and Aβ1-42 fibril formation. It mainly inhibited the elongation phase of Aβ1-42 fibril formation kinetics, but not the lag phase. Western blotting results showed that it did not inhibit its oligomerization process, rather increased it. Additionally, GaCl-Pc destabilized preformed Aβ1- 42 fibrils dose-dependently in vitro condition, and decreased Aβ levels in the brain slice culture of APP transgenic AD model mice (J20 strain). Near-infrared scanning results showed that GaCl-Pc had the ability to bind to Aβ1-42. MTT assay demonstrated that GaCl-Pc did not have toxicity towards a neuronal cell line (A1) in culture rather, showed protective effects on Aβ-induced toxicity. Moreover, it dosedependently decreased Aβ-induced reactive oxygen species levels in A1 culture. Conclusion: Thus, our result demonstrated that GaCl-Pc decreased Aβ aggregation and destabilized the preformed fibrils. Since cationic molecules show a better ability to cross the blood-brain barrier, cationic GaCl-Pc could be important for the therapy of AD.
    Type of Medium: Online Resource
    ISSN: 1567-2050
    URL: Article
    DOI: 10.2174/1567205017666201008112002
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2020
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  • 4
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    Potential role of tubulin glutamylation in neurodegenerative diseases
    Medknow ; 2023
    In:  Neural Regeneration Research
    Details
    In: Neural Regeneration Research, Medknow
    Type of Medium: Online Resource
    ISSN: 1673-5374 , 1876-7958
    URL: Article
    DOI: 10.4103/1673-5374.385859
    Language: English
    Publisher: Medknow
    Publication Date: 2023
    detail.hit.zdb_id: 2388460-5
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  • 5
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    Time-Dependent Analysis of Plasmalogens in the Hippocampus of an Alzheimer’s Disease Mouse Model: A Role of Ethanolamine Plasmalogen
    MDPI AG ; 2021
    In:  Brain Sciences Vol. 11, No. 12 ( 2021-12-02), p. 1603-
    Details
    In: Brain Sciences, MDPI AG, Vol. 11, No. 12 ( 2021-12-02), p. 1603-
    Abstract: Plasmalogens are alkenyl-acyl glycerophospholipids and decreased in post-mortem Alzheimer’s disease (AD) brains. The aim of this study is to investigate the time-dependent changes of plasmalogens in the hippocampus of an AD model mouse (J20). Plasmalogen levels at 3, 6, 9, 12 and 15 months were analyzed by liquid-chromatography-targeted-multiplexed-selected-reaction-monitoring-tandem-mass-spectrometry (LC-SRM/MS). Reactive oxygen species (ROS) levels were evaluated using dichlorofluorescein diacetate (DCF-DA). Plasmalogen synthesizing enzyme glycerone-phosphate O-acyltransferase (GNPAT) and late endosome marker Rab7 levels were quantified by Western blotting. GNPAT localization, changes of neuronal and glial cell numbers were evaluated by immunostaining. Compared to wild-type mice (WT), total plasmalogen-ethanolamine, but not plasmalogen-choline levels, were increased at 9 months and subsequently decreased at 15 months in J20 mice. A principal component analysis of plasmalogen-ethanolamine species could separate WT and J20 mice both at 9 and 15 months. Both GNPAT and Rab7 protein were increased in J20 mice at 9 months, whereas GNPAT was decreased at 15 months. ROS levels were increased in J20 mice except for 9 months. Our results suggest that increased plasmalogen-ethanolamine could counteract ROS levels and contribute to the phagocytosis process in J20 mice at 9 months. Such results might indicate a transient protective response of plasmalogen-ethanolamine in AD conditions.
    Type of Medium: Online Resource
    ISSN: 2076-3425
    URL: Article
    DOI: 10.3390/brainsci11121603
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2651993-8
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  • 6
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    Alzheimer’s Amyloid β Peptide Induces Angiogenesis in an Alzheimer’s Disease Model Mouse through Placental Growth Factor and Angiopoietin 2 Expressions
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 5 ( 2023-02-24), p. 4510-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 5 ( 2023-02-24), p. 4510-
    Abstract: Increased angiogenesis, especially the pathological type, has been documented in Alzheimer’s disease (AD) brains, and it is considered to be activated due to a vascular dysfunction-mediated hypoxic condition. To understand the role of the amyloid β (Aβ) peptide in angiogenesis, we analyzed its effects on the brains of young APP transgenic AD model mice. Immunostaining results revealed that Aβ was mainly localized intracellularly, with very few immunopositive vessels, and there was no extracellular deposition at this age. Solanum tuberosum lectin staining demonstrated that compared to their wild-type littermates, the vessel number was only increased in the cortex of J20 mice. CD105 staining also showed an increased number of new vessels in the cortex, some of which were partially positive for collagen4. Real-time PCR results demonstrated that placental growth factor (PlGF) and angiopoietin 2 (AngII) mRNA were increased in both the cortex and hippocampus of J20 mice compared to their wild-type littermates. However, vascular endothelial growth factor (VEGF) mRNA did not change. Immunofluorescence staining confirmed the increased expression of PlGF and AngII in the cortex of the J20 mice. Neuronal cells were positive for PlGF and AngII. Treatment of a neural stem cell line (NMW7) with synthetic Aβ1–42 directly increased the expression of PlGF and AngII, at mRNA levels, and AngII at protein levels. Thus, these pilot data indicate that pathological angiogenesis exists in AD brains due to the direct effects of early Aβ accumulation, suggesting that the Aβ peptide regulates angiogenesis through PlGF and AngII expression.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24054510
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
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  • 7
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    A carboxylated Zn‐phthalocyanine inhibits fibril formation of Alzheimer's amyloid β peptide
    Wiley ; 2015
    In:  The FEBS Journal Vol. 282, No. 3 ( 2015-02), p. 463-476
    Details
    In: The FEBS Journal, Wiley, Vol. 282, No. 3 ( 2015-02), p. 463-476
    Abstract: Amyloid β (Aβ), a 39–42 amino acid peptide derived from amyloid precursor protein, is deposited as fibrils in Alzheimer's disease brains, and is considered to play a major role in the pathogenesis of the disease. We have investigated the effects of a water‐soluble Zn‐phthalocyanine, ZnPc( COON a) 8 , a macrocyclic compound with near‐infrared optical properties, on Aβ fibril formation in vitro . A thioflavin T fluorescence assay showed that ZnPc( COON a) 8 significantly inhibited Aβ fibril formation, increasing the lag time and dose‐dependently decreasing the plateau level of fibril formation. Moreover, it destabilized pre‐formed Aβ fibrils, resulting in an increase in low‐molecular‐weight species. After fibril formation in the presence of ZnPc( COON a) 8 , immunoprecipitation of Aβ 1‐42 using Aβ‐specific antibody followed by near‐infrared scanning demonstrated binding of ZnPc( COON a) 8 to Aβ 1‐42 . A study using the hydrophobic fluorescent probe 8‐anilino‐1‐naphthalenesulfonic acid showed that ZnPc( COON a) 8 decreased the hydrophobicity during Aβ 1‐42 fibril formation. CD spectroscopy showed an increase in the α helix structure and a decrease in the β sheet structure of Aβ 1‐40 in fibril‐forming buffer containing ZnPc( COON a) 8 . SDS/PAGE and a dot‐blot immunoassay showed that ZnPc( COON a) 8 delayed the disappearance of low‐molecular‐weight species and the appearance of higher‐molecular‐weight oligomeric species of Aβ 1‐42 . A cell viability assay showed that ZnPc( COON a) 8 was not toxic to a neuronal cell line (A1), but instead protected A1 cells against Aβ 1‐42 ‐induced toxicity. Overall, our results indicate that ZnPc( COON a) 8 binds to Aβ and decreases the hydrophobicity, and this change is unfavorable for Aβ oligomerization and fibril formation.
    Type of Medium: Online Resource
    ISSN: 1742-464X , 1742-4658
    URL: Issue
    URL: Article
    DOI: 10.1111/febs.2015.282.issue-3
    DOI: 10.1111/febs.13151
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2172518-4
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  • 8
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    Rho-Kinase inhibition decreases focal cerebral ischemia-induced glial activation in rats
    SAGE Publications ; 2022
    In:  Journal of Central Nervous System Disease Vol. 14 ( 2022-01), p. 117957352211239-
    Details
    In: Journal of Central Nervous System Disease, SAGE Publications, Vol. 14 ( 2022-01), p. 117957352211239-
    Abstract: Rho-kinase inhibition in a rat middle cerebral artery occlusion (MCAO) model is reported to improve neurological functions and decrease infarction size. Objective The objective of this study is to investigate the underlying mechanisms of such improvement by evaluating the effects of Rho-kinase inhibition on astrocytes and microglial accumulation and activation in this condition. Methods Adult male Sprague-Dawley (SD) rats were used to generate the MCAO model, which received an I.P injection of a chemical Rho-kinase inhibitor (Fasudil- 5 mg/kg/day) or vehicle (PBS) for 2 and 4 days. Results Fasudil treatment significantly decreased the stroke volumes and water content in the lesion areas, as revealed by MRI. Immunostaining and Western blotting results demonstrated that Fasudil significantly decreased the levels of Aquaporin-4, a water channel protein. The number of GFAP + astrocytes and Iba-1 + macrophage/microglia was decreased in the lesion areas. Proinflammatory transcription factor NF-κB protein levels were decreased in the Fasudil group 2 days after MCAO. Also, proinflammatory mediators including TNF-α, IL-1β, and iNOS levels were decreased. In vitro migration study using a human microglial cell line (HMO6) confirmed the inhibitory effects of Fasudil on the process. Fasudil also decreased combined IL-1β and IFNγ-induced NF-κB nuclear translocation in HMO6. Moreover, Fasudil transiently decreased combined IL-1β and IFNγ-induced iNOS, TNFα, and IL-1β mRNA levels in HMO6. Conclusion Our study demonstrates the inhibitory effects of Rho-kinase on NF-κB-mediated glial activation and cerebral edema, which might be a promising therapeutic target in acute cerebral ischemia conditions.
    Type of Medium: Online Resource
    ISSN: 1179-5735 , 1179-5735
    URL: Article
    DOI: 10.1177/11795735221123910
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2586873-1
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  • 9
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    Alteration of Neural Stem Cell Functions in Ataxia and Male Sterility Mice: A Possible Role of β-Tubulin Glutamylation in Neurodegeneration
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 1 ( 2021-01-14), p. 155-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 1 ( 2021-01-14), p. 155-
    Abstract: Ataxia and Male Sterility (AMS) is a mutant mouse strain that contains a missense mutation in the coding region of Nna1, a gene that encodes a deglutamylase. AMS mice exhibit early cerebellar Purkinje cell degeneration and an ataxic phenotype in an autosomal recessive manner. To understand the underlying mechanism, we generated neuronal stem cell (NSC) lines from wild-type (NMW7), Nna1 mutation heterozygous (NME), and Nna1 mutation homozygous (NMO1) mouse brains. The NNA1 levels were decreased, and the glutamylated tubulin levels were increased in NMO1 cultures as well as in the cerebellum of AMS mice at both 15 and 30 days of age. However, total β-tubulin protein levels were not altered in the AMS cerebellum. In NMO1 neurosphere cultures, β-tubulin protein levels were increased without changes at the transcriptional level. NMO1 grew faster than other NSC lines, and some of the neurospheres were attached to the plate after 3 days. Immunostaining revealed that SOX2 and nestin levels were decreased in NMO1 neurospheres and that the neuronal differentiation potentials were reduced in NMO1 cells compared to NME or NMW7 cells. These results demonstrate that the AMS mutation decreased the NNA1 levels and increased glutamylation in the cerebellum of AMS mice. The observed changes in glutamylation might alter NSC properties and the neuron maturation process, leading to Purkinje cell death in AMS mice.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10010155
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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