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

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; Pilar Martinez-Martinez

doi:10.1186/s13195-021-00780-0

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

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 VerhaagenMario Losen, Erhard Bieberich, Pilar Martinez-Martinez

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Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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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.

Originele taal-2	Engels
Pagina's (van-tot)	45
Tijdschrift	Alzheimer's Research & Therapy
Volume	13
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1186/s13195-021-00780-0
Status	Gepubliceerd - jan. 2021

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Crivelli, S. M., Luo, Q., Stevens, J. A. A., Giovagnoni, C., van Kruining, D., Bode, G., den Hoedt, S., Hobo, B., Scheithauer, A.-L., Walter, J., Mulder, M. T., Exley, C., Mold, M., Mielke, M. M., De Vries, H. E., Wouters, K., van den Hove, D. L. A., Berkes, D., Ledesma, M. D., ... Martinez-Martinez, P. (2021). CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease. Alzheimer's Research & Therapy, 13(1), 45. https://doi.org/10.1186/s13195-021-00780-0

@article{2aa74c3c089a4496afc7010e3537ce76,

title = "CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease",

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.",

author = "Crivelli, {Simone M} and Qian Luo and Stevens, {Jo A A} and Caterina Giovagnoni and {van Kruining}, Daan and Gerard Bode and {den Hoedt}, Sandra and Barbara Hobo and Anna-Lena Scheithauer and Jochen Walter and Mulder, {Monique T} and Christopher Exley and Matthew Mold and Mielke, {Michelle M} and {De Vries}, {Helga E} and Kristiaan Wouters and {van den Hove}, {Daniel L A} and Dusan Berkes and Ledesma, {Mar{\'i}a Dolores} and Joost Verhaagen and Mario Losen and Erhard Bieberich and Pilar Martinez-Martinez",

year = "2021",

month = jan,

doi = "10.1186/s13195-021-00780-0",

language = "English",

volume = "13",

pages = "45",

journal = "Alzheimer's Research & Therapy",

issn = "1758-9193",

publisher = "BioMed Central",

number = "1",

}

Crivelli, SM, Luo, Q, Stevens, JAA, Giovagnoni, C, van Kruining, D, Bode, G, den Hoedt, S, Hobo, B, Scheithauer, A-L, Walter, J, Mulder, MT, Exley, C, Mold, M, Mielke, MM, De Vries, HE, Wouters, K, van den Hove, DLA, Berkes, D, Ledesma, MD, Verhaagen, J, Losen, M, Bieberich, E & Martinez-Martinez, P 2021, 'CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease', Alzheimer's Research & Therapy, vol. 13, nr. 1, blz. 45. https://doi.org/10.1186/s13195-021-00780-0

TY - JOUR

T1 - CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease

AU - Crivelli, Simone M

AU - Luo, Qian

AU - Stevens, Jo A A

AU - Giovagnoni, Caterina

AU - van Kruining, Daan

AU - Bode, Gerard

AU - den Hoedt, Sandra

AU - Hobo, Barbara

AU - Scheithauer, Anna-Lena

AU - Walter, Jochen

AU - Mulder, Monique T

AU - Exley, Christopher

AU - Mold, Matthew

AU - Mielke, Michelle M

AU - De Vries, Helga E

AU - Wouters, Kristiaan

AU - van den Hove, Daniel L A

AU - Berkes, Dusan

AU - Ledesma, María Dolores

AU - Verhaagen, Joost

AU - Losen, Mario

AU - Bieberich, Erhard

AU - Martinez-Martinez, Pilar

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

U2 - 10.1186/s13195-021-00780-0

DO - 10.1186/s13195-021-00780-0

M3 - Article

C2 - 33597019

SN - 1758-9193

VL - 13

SP - 45

JO - Alzheimer's Research & Therapy

JF - Alzheimer's Research & Therapy

IS - 1

ER -

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

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