Astrocytic ceramide as possible indicator of neuroinflammation

Abstract

Background Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), and frontotemporal lobar dementia (FTLD) are characterized by progressive neuronal loss but differ in their underlying pathological mechanisms. However, neuroinflammation is commonly observed within these different forms of dementia. Recently, it has been suggested that an altered sphingolipid metabolism may contribute to the pathogenesis of a variety of neurodegenerative conditions. Especially ceramide, the precursor of all complex sphingolipids, is thought to be associated with pro-apoptotic cellular processes, thereby propagating neurodegeneration and neuroinflammation, although it remains unclear to what extent. The current pathological study therefore investigates whether increased levels of ceramide are associated with the degree of neuroinflammation in various neurodegenerative disorders. Methods Immunohistochemistry was performed on human post-mortem tissue of PDD and FTLD Pick’s disease cases, which are well-characterized cases of dementia subtypes differing in their neuroinflammatory status, to assess the expression and localization of ceramide, acid sphingomyelinase, and ceramide synthase 2 and 5. In addition, we determined the concentration of sphingosine, sphingosine-1-phosphate (S1P), and ceramide species differing in their chain-length in brain homogenates of the post-mortem tissue using HPLC-MS/MS. Results Our immunohistochemical analysis reveals that neuroinflammation is associated with increased ceramide levels in astrocytes in FTLD Pick’s disease. Moreover, the observed increase in ceramide in astrocytes correlates with the expression of ceramide synthase 5. In addition, HPLC-MS/MS analysis shows a shift in ceramide species under neuroinflammatory conditions, favoring pro-apoptotic ceramide. Conclusions Together, these findings suggest that detected increased levels of pro-apoptotic ceramide might be a common denominator of neuroinflammation in different neurodegenerative diseases. Electronic supplementary material The online version of this article (10.1186/s12974-019-1436-1) contains supplementary material, which is available to authorized users.

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

“…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.…”

Sphingolipids and Diagnosis, Prognosis, and Organ Damage in Systemic Lupus Erythematosus

“…In addition, studies have shown that sphingolipids play a significant role in the pathogenesis of several neuroinflammatory disorders such as Alzheimer's disease and Parkinson's disease (68,69). During early phases of neuroinflammation, astrocytic sphingolipid alterations, which include an increase in ceramide and decrease in SKs that generate S1P were reported (68,70). More information regarding the role of sphingolipids in neuroinflammation were reviewed previously (68,69,71).…”

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

“…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 carry Aβ peptides (86).…”