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 ORCID: https://orcid.org/0000-0002-5116-7607, Mold, M, Mielke, MM, De Vries, HE, Wouters, K, van den Hove, DLA, Berkes, D, Ledesma, MD, Verhaagen, J, Losen, M, Bieberich, E and Martinez-Martinez, P (2021) CERTL reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimer's disease. Alzheimers Research and Therapy, 13 (1). 45 -?.

[img]
Preview
Text
CERTsubLsub reduces C16 ceramide, amyloid-β levels, and inflammation in a model of Alzheimers disease.pdf - Published Version
Available under License Creative Commons Attribution.

Download (7MB) | Preview

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.

Item Type: Article
Additional Information: This is the final published version (version of record). It was first published online via xx at xxx - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: 5xFAD, Adeno-associated virus (AAV), Alzheimer’s disease (AD), Amyloid-β plaques, Ceramide, Ceramide transporter protein (CERT), Microglia, Neuroinflammation, Sphingomyelin
Subjects: R Medicine > RC Internal medicine > RC346 Neurology. Diseases of the nervous system, including speech disorders
R Medicine > RC Internal medicine > RC521 Dementia
Divisions: Faculty of Natural Sciences > School of Life Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 16 Mar 2021 14:40
Last Modified: 11 Jun 2021 15:09
URI: https://eprints.keele.ac.uk/id/eprint/9261

Actions (login required)

View Item View Item