scholarly journals Jowiseungchungtang Inhibits Amyloid-β Aggregation and Amyloid-β-Mediated Pathology in 5XFAD Mice

2018 ◽  
Vol 19 (12) ◽  
pp. 4026 ◽  
Author(s):  
Soo Shin ◽  
Yu-on Jeong ◽  
Seong Jeon ◽  
Sujin Kim ◽  
Seong-kyung Lee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Loss ◽  
Amyloid Β ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Aβ Aggregation ◽  
5Xfad Mice

Alzheimer’s disease (AD) is a neurodegenerative disease, which is accompanied by memory loss and cognitive dysfunction. Although a number of trials to treat AD are in progress, there are no drugs available that inhibit the progression of AD. As the aggregation of amyloid-β (Aβ) peptides in the brain is considered to be the major pathology of AD, inhibition of Aβ aggregation could be an effective strategy for AD treatment. Jowiseungchungtang (JWS) is a traditional oriental herbal formulation that has been shown to improve cognitive function in patients or animal models with dementia. However, there are no reports examining the effects of JWS on Aβ aggregation. Thus, we investigated whether JWS could protect against both Aβ aggregates and Aβ-mediated pathology such as neuroinflammation, neurodegeneration, and impaired adult neurogenesis in 5 five familial Alzheimer’s disease mutations (5XFAD) mice, an animal model for AD. In an in vitro thioflavin T assay, JWS showed a remarkable anti-Aβ aggregation effect. Histochemical analysis indicated that JWS had inhibitory effects on Aβ aggregation, Aβ-induced pathologies, and improved adult hippocampal neurogenesis in vivo. Taken together, these results suggest the therapeutic possibility of JWS for AD targeting Aβ aggregation, Aβ-mediated neurodegeneration, and impaired adult hippocampal neurogenesis.

scholarly journals Red Ginseng Attenuates Aβ-Induced Mitochondrial Dysfunction and Aβ-mediated Pathology in an Animal Model of Alzheimer’s Disease

2019 ◽  
Vol 20 (12) ◽  
pp. 3030 ◽  
Author(s):  
Soo Jung Shin ◽  
Seong Gak Jeon ◽  
Jin-il Kim ◽  
Yu-on Jeong ◽  
Sujin Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Formation ◽  
Experimental Models ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Red Ginseng ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

Extraction of Polysaccharides From Bletilla Striata Using a Modified Low-temperature Method and Evaluation of Their Efficacy Against Alzheimer’s Disease

2021 ◽  
Author(s):  
Yi-Wen Lin ◽  
Chih-Hsiang Fang ◽  
Hung-Hsiang Liao ◽  
Feng Huei Lin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Low Temperature ◽  
Memory Loss ◽  
Amyloid Β ◽  
Ulcer Bleeding ◽  
Bletilla Striata ◽  
Temperature Method

Abstract Background: Amyloid-β (Aβ) peptides play a key role in Alzheimer’s disease (AD), the most common type of dementia. AD is characterized by progressive cognitive and memory loss accompanied by personality changes. Bletilla striata, a traditional Chinese medicine, has been widely used in Eastern Asian countries for alimentary canal damage, ulcer, bleeding, bruises, and burns. in this study, we investigated whether BSP could prevent the ROS from Aβ and the possibility to recover from the disease by memory improvement.Methods: In this study, a polysaccharide from Bletilla striata (BSP) with strong antioxidant and anti-inflammatory properties was extracted following a low-temperature method and tested for its efficacy against AD in vitro using N2a and BV-2 cells and in vivo using AD rats.Results: The characterization of the extracted BSP for its molecular structure and the functional group demonstrated the efficiency of the modified method to retain its bioactivity. In vitro, BSP reduced ROS levels in N2a cells and the expression levels of inflammatory-related genes in BV-2 cells treated with Aβ fibrils. In vivo, BSP recovered the learning memory, ameliorated the morphological damages in the hippocampus and cortex, and reduced the expression of the β-secretase protein in AlCl3-induced AD rats.Conclusions: To the best of our knowledge, this is the first study of BSP applicating in AD. Collectively, these findings demonstrated the efficacy of BSP to prevent and alleviate the effects of AD.

scholarly journals CERTL Reduces C16 Ceramide, Amyloid-β Levels and Inflammation in a Model of Alzheimer's Disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Deregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction animal were challenged with behavior tests for memory, anxiety and locomotion. At week twelve brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male transgenic mice, modelling familial AD (5xFAD). CERTL in vivo over-expression has a mild effect on animal locomotion and decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

scholarly journals CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Simone M. Crivelli ◽  
Qian Luo ◽  
Jo A.A. Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain. Methods A plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno-associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety, and locomotion. At week 12, brains were investigated for sphingolipid levels by mass spectrometry, plaques, and neuroinflammation by immunohistochemistry, gene expression, and/or immunoassay. Results Here, we report that CERTL binds to APP, modifies Aβ aggregation, and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation, and modulates microglia by decreasing their pro-inflammatory phenotype. Conclusion Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

scholarly journals CERTL reduces C16 ceramide, amyloid-β levels and inflammation in a model of Alzheimer's disease

2021 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo A.A. Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers which are crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: A plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety and locomotion. At week twelve, brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

scholarly journals Omega-3 Fatty Acid-Type Docosahexaenoic Acid Protects against Aβ-Mediated Mitochondrial Deficits and Pathomechanisms in Alzheimer’s Disease-Related Animal Model

2020 ◽  
Vol 21 (11) ◽  
pp. 3879
Author(s):  
Yong Ho Park ◽  
Soo Jung Shin ◽  
Hyeon soo Kim ◽  
Sang Bum Hong ◽  
Sujin Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Docosahexaenoic Acid ◽  
Cell Model ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Omega 3 ◽  
Ht22 Cells

It has been reported that damage to the mitochondria affects the progression of Alzheimer’s disease (AD), and that mitochondrial dysfunction is improved by omega-3. However, no animal or cell model studies have confirmed whether omega-3 inhibits AD pathology related to mitochondria deficits. In this study, we aimed to (1) identify mitigating effects of endogenous omega-3 on mitochondrial deficits and AD pathology induced by amyloid beta (Aβ) in fat-1 mice, a transgenic omega-3 polyunsaturated fatty acids (PUFAs)-producing animal; (2) identify if docosahexaenoic acid (DHA) improves mitochondrial deficits induced by Aβ in HT22 cells; and (3) verify improvement effects of DHA administration on mitochondrial deficits and AD pathology in B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD), a transgenic Aβ-overexpressing model. We found that omega-3 PUFAs significantly improved Aβ-induced mitochondrial pathology in fat-1 mice. In addition, our in vitro and in vivo findings demonstrate that DHA attenuated AD-associated pathologies, such as mitochondrial impairment, Aβ accumulation, neuroinflammation, neuronal loss, and impairment of adult hippocampal neurogenesis.

scholarly journals Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

2020 ◽  
Author(s):  
Evgenia Salta ◽  
Hannah Walgrave ◽  
Sriram Balusu ◽  
Elke Vanden Eynden ◽  
Sarah Snoeck ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Memory Decline ◽  
Human Neural Stem Cells ◽  
Neurogenic Niche

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

scholarly journals CERTL reduces C16 ceramide, amyloid-β levels and inflammation in a model of Alzheimer's disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Dysregulation of ceramide and sphingomyelin levels have been suggested to contribute to the pathogenesis of Alzheimer’s disease (AD). Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells. Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTL with amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescence in HEK cells. The recombinant CERTL protein was employed to study interaction of CERTL with amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes in Aβ toxicity in neuroblastoma cells. CERTL was overexpressed in neurons by adeno associated virus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction, animals were challenged with behavior tests for memory, anxiety and locomotion. At week twelve, brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results: Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male 5xFAD mice. CERTL in vivo over-expression has a mild effect on animal locomotion, decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstrate a crucial role of CERTL in regulating ceramide levels in the brain, in amyloid plaque formation and neuroinflammation, thereby opening research avenues for therapeutic targets of AD and other neurodegenerative diseases.

scholarly journals CERTL Reduces C16 Ceramide, Amyloid-β Levels and Inflammation in a Model of Alzheimer's Disease

2020 ◽  
Author(s):  
Simone Mwenda Crivelli ◽  
Qian Luo ◽  
Jo Stevens ◽  
Caterina Giovagnoni ◽  
Daan van Kruining ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Aggregation ◽  
The Brain

Abstract Background: Deregulation of ceramide and sphingomyelinlevels have been suggested tocontribute tothe pathogenesis of Alzheimer’s disease (AD).Ceramide transfer proteins (CERTs) are ceramide carriers, crucial for ceramide and sphingomyelin balance in cells.Extracellular forms of CERTs co-localize with amyloid-β (Aβ) plaques in AD brains. To date, the significance of these observations for the pathophysiology of AD remains uncertain.Methods: The plasmid expressing CERTL, the long isoform of CERTs, was used to study the interaction of CERTLwith amyloid precursor protein (APP) by co-immunoprecipitation and immunofluorescencein HEK cells.The recombinant CERTL protein wasemployed to study interaction of CERTLwith amyloid-β (Aβ), Aβ aggregation process in presence of CERTL, and the resulting changes inAβ toxicity in neuroblastoma cells. CERTLwas overexpressed in neurons by adeno associatedvirus (AAV) in a familial mouse model of familial AD (5xFAD). Ten weeks after transduction animal were challenged with behavior tests for memory, anxiety and locomotion. At week twelve brains were investigated for sphingolipid levels by mass spectrometry, plaques and neuroinflammation by immunohistochemistry, gene expression and/or immunoassay.Results:Here, we report that CERTL, binds to APP, modifies Aβ aggregation and reduces Aβ neurotoxicity in vitro. Furthermore, we show that intracortical injection of AAV, mediating the expression of CERTL, decreases levels of ceramide d18:1/16:0 and increases sphingomyelin levels in the brain of male transgenic mice, modelling familial AD (5xFAD). CERTLin vivo over-expression hasa mild effect on animal locomotion and decreases Aβ formation and modulates microglia by decreasing their pro-inflammatory phenotype.Conclusion: Our results demonstratea crucial role of CERTL in regulatingceramidelevels in the brain, in amyloid plaque formation and neuroinflammation,thereby opening research avenuesfor therapeutic targets of AD and other neurodegenerative diseases.

scholarly journals Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shady Estfanous ◽  
Kylene P. Daily ◽  
Mostafa Eltobgy ◽  
Nicholas P. Deems ◽  
Midhun N. K. Anne ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
Tissue Sections ◽  
Cargo Receptor ◽  
5Xfad Mouse ◽  
Aβ Degradation

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in AD.

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