Ceramide and Related‐Sphingolipid Levels Are Not Altered in Disease‐Associated Brain Regions of APPSL and APPSL/PS1M146L Mouse Models of Alzheimer′s Disease: Relationship with the Lack of Neurodegeneration?

Barrier, Laurence; Fauconneau, Bernard; Noël, Anastasia; Ingrand, Sabrina

doi:10.4061/2011/920958

Cited by 19 publications

(13 citation statements)

References 66 publications

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“…These alterations were exacerbated in aged transgenic mice as compared with wild type controls, suggesting a correlation between aged cortical neuronal lipid raft detriment and AD phenotype. Alterations in the contents of long-chain ceramides and cholesterol have also been observed in another transgenic mouse model of AD (APP SL /PS1Ki), in correlation with similar results obtained in human AD cortex [80,81].…”

Section: Lipid Raft Stability and Progressive Neurodegenerationsupporting

confidence: 84%

Lipid Raft Alterations in Aged-Associated Neuropathologies

Marín¹,

Fabelo²,

Fernández-Echevarría³

et al. 2016

CAR

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Lipid rafts are membrane microdomains particularly enriched in cholesterol, sphingolipids and saturated fatty acids. These microstructures play a key role in a plethora of mechanisms involved in cell signaling, synapsis, cell-cell communication and cell survival. In the last years, increasing evidence indicate that lipid rafts may be altered in age-related neuropathologies, such as Alzheimer's disease and Parkinson disease even at asymptomatic stages. In particular, important changes in raft lipid composition are observed with the progression of these diseases, then inducing alterations in their physicochemical properties. Furthermore, these phenomena contribute to neuropathological events related to amyloidogenesis, aberrant protein aggregation and toxic cell signalling. In this review, we discuss some relevant data on the age-related molecular changes occurring in lipid rafts since the first stages of these neurodegenerative diseases. Further characterization of specific parameters associated with alterations of these microdomains may provide potential tools of diagnosis and prediction of these neuropathologies.

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Section: Lipid Raft Stability and Progressive Neurodegenerationsupporting

confidence: 84%

Lipid Raft Alterations in Aged-Associated Neuropathologies

Marín¹,

Fabelo²,

Fernández-Echevarría³

et al. 2016

CAR

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“…Furthermore, an accumulating body of evidence consistently reported a global rise inCer levels in speci c brain regions of AD patients (13,71,72). In agreement with these observations, we found that 5xFAD transgenic mice at 6 months of age also showed an increase of Cer d18:1/16:0 in the cortex and ofseveral Cerspecies in the hippocampus (Cer d18:1/16:0, Cer d18:1/18:1, Cer d18:1/20:0 andCer d18:1/22:0).Previously, other studies showed increased brain Cer levels indifferenttransgenic AD models (APP, PS1, and PS1-APP mutated mice) (73).This suggests that there is a causal relationship between amyloid pathology and Cer imbalance.…”

Section: Discussionmentioning

confidence: 60%

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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“…The APPSL–PS1Ki mouse model is differentiated from other AD mouse models in its drastic neuronal loss, in part due to N-terminal truncated amyloid-β variants. Notably, in other mouse models, including APPSL, APPSL–PS1M146L and APPsw, in which there is not extensive early neuronal loss, ceramides were not found to be increased in the cortex or hippocampus [48,49]. Thus, similar to the discussion with tau above, amyloid-β-induced ceramide increases can lead to subsequent neurodegeneration.…”

Section: Cell and Animal Studies Suggest Sphingolipids Contribute To Almentioning

confidence: 60%

Could plasma sphingolipids be diagnostic or prognostic biomarkers for Alzheimer’s disease?

Mielke

Haughey

2012

Clinical Lipidology

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Understanding the etiopathological processes of Alzheimer’s disease (AD) in the preclinical and early clinical stages will be important in developing new therapeutic targets and biomarkers. There is growing consensus that nonamyloid targets will be necessary to reverse or slow AD progression. Lipidomic, metabolomic and targeted approaches have identified pathways and products of sphingolipid metabolism that are altered early in the course of AD and contribute to the neuropathological alterations associated with AD, including amyloid-β production, tau formation and neurodegeneration. In this article, we briefly review the current literature on the role of sphingolipids in the underlying pathophysiology of AD, and then discuss the current state of translating these findings to clinical populations and the potential utility of plasma sphingolipids as diagnostic and/or prognostic indicators of AD.

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Ceramide and Related‐Sphingolipid Levels Are Not Altered in Disease‐Associated Brain Regions of APP^SL and APP^SL/PS1^M146L Mouse Models of Alzheimer′s Disease: Relationship with the Lack of Neurodegeneration?

Cited by 19 publications

References 66 publications

Lipid Raft Alterations in Aged-Associated Neuropathologies

Lipid Raft Alterations in Aged-Associated Neuropathologies

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

Could plasma sphingolipids be diagnostic or prognostic biomarkers for Alzheimer’s disease?

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