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Your search keyword '"Daniel L. A. van den Hove"' showing total 2 results
Start Over Author "Daniel L. A. van den Hove" Topic alzheimer's disease (ad)
2 results on '"Daniel L. A. van den Hove"'

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

Author

Simone M. Crivelli, Qian Luo, Jo A.A. Stevens, Caterina Giovagnoni, Daan van Kruining, Gerard Bode, Sandra den Hoedt, Barbara Hobo, Anna-Lena Scheithauer, Jochen Walter, Monique T. Mulder, Christopher Exley, Matthew Mold, Michelle M. Mielke, Helga E. De Vries, Kristiaan Wouters, Daniel L. A. van den Hove, Dusan Berkes, María Dolores Ledesma, Joost Verhaagen, Mario Losen, Erhard Bieberich, and Pilar Martinez-Martinez

Subjects
Ceramide, Sphingomyelin, Ceramide transporter protein (CERT), Adeno-associated virus (AAV), Alzheimer’s disease (AD), 5xFAD, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

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.

Published
2021
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2. CERT

Author

Simone M, Crivelli, Qian, Luo, Jo A A, Stevens, Caterina, Giovagnoni, Daan, van Kruining, Gerard, Bode, Sandra, den Hoedt, Barbara, Hobo, Anna-Lena, Scheithauer, Jochen, Walter, Monique T, Mulder, Christopher, Exley, Matthew, Mold, Michelle M, Mielke, Helga E, De Vries, Kristiaan, Wouters, Daniel L A, van den Hove, Dusan, Berkes, María Dolores, Ledesma, Joost, Verhaagen, Mario, Losen, Erhard, Bieberich, and Pilar, Martinez-Martinez

Subjects
Inflammation, Male, Sphingomyelin, Amyloid beta-Peptides, Research, Adeno-associated virus (AAV), Brain, Alzheimer’s disease (AD), Amyloid-β plaques, Mice, Transgenic, Plaque, Amyloid, Ceramides, 5xFAD, Ceramide, Amyloid beta-Protein Precursor, Disease Models, Animal, Mice, Neuroinflammation, Alzheimer Disease, Animals, Microglia, Ceramide transporter protein (CERT)
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. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-021-00780-0.

Published
2020

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