Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Elsherbini, Ahmed; Kirov, Alexander S.; Dinkins, Michael B.; Wang, Guanghu; Qin, Haiyan; Zhu, Zhihui; Tripathi, Priyanka; Crivelli, Simone M.; Bieberich, Erhard

doi:10.1186/s40478-020-00931-8

Cited by 45 publications

(49 citation statements)

References 82 publications

(99 reference statements)

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“…During in ammation astrocytes are enriched in Cer. They seem to produce the pro-apoptotic Cer d18:1/16:0 (85,86). Further, reactive astrocytes release extracellular vesicle enriched in ceramide that carryAβ peptides (86).These speci c extracellular vesiclesisolated from brains of 5xFAD mice showed to be particularly toxic for neurons.…”

Section: Discussionmentioning

confidence: 99%

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

Crivelli

Luo

Stevens

et al. 2020

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

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

Crivelli

Luo

Stevens

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…They seem to produce the pro-apoptotic Cer d18:1/16:0 (85,86). Further, reactive astrocytes release extracellular vesicle enriched in ceramide that carry Aβ peptides (86). These speci c extracellular vesicles isolated from brains of 5xFAD mice showed to be particularly toxic for neurons.…”

Section: Discussionmentioning

confidence: 99%

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

Crivelli

Luo

Stevens

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

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“…The exchange effects induced by such types of intercellular communication can be variable [ 96 ]. In aged AD patients, most exosomes, released by reactive A1 astrocytes, activate various neurotoxic mechanisms, inducing fragmentation and death of neurons [ 96 , 97 ].…”

Section: The Role Of Astrocytes In Alzheimer’s Diseasementioning

confidence: 99%

Astrocytes: News about Brain Health and Diseases

Meldolesi

2020

Biomedicines

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Astrocytes, the most numerous glial cells in the brains of humans and other mammalian animals, have been studied since their discovery over 100 years ago. For many decades, however, astrocytes were believed to operate as a glue, providing only mechanical and metabolic support to adjacent neurons. Starting from a “revolution” initiated about 25 years ago, numerous astrocyte functions have been reconsidered, some previously unknown, others attributed to neurons or other cell types. The knowledge of astrocytes has been continuously growing during the last few years. Based on these considerations, in the present review, different from single or general overviews, focused on six astrocyte functions, chosen due in their relevance in both brain physiology and pathology. Astrocytes, previously believed to be homogeneous, are now recognized to be heterogeneous, composed by types distinct in structure, distribution, and function; their cooperation with microglia is known to govern local neuroinflammation and brain restoration upon traumatic injuries; and astrocyte senescence is relevant for the development of both health and diseases. Knowledge regarding the role of astrocytes in tauopathies and Alzheimer’s disease has grow considerably. The multiple properties emphasized here, relevant for the present state of astrocytes, will be further developed by ongoing and future studies.

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Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity

Cited by 45 publications

References 82 publications

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

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

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

Astrocytes: News about Brain Health and Diseases

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