Abstract
BackgroundNeurodegenerative 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.MethodsImmunohistochemistry 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.ResultsOur 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.ConclusionsTogether, these findings suggest that detected increased levels of pro-apoptotic ceramide might be a common denominator of neuroinflammation in different neurodegenerative diseases.
Highlights
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
Neuroinflammation is associated with increased ceramide levels in astrocytes in FTD Pick’s disease We first examined the degree of neuroinflammation in frontotemporal dementia Pick’s disease (FTD-Pi), PDD, and non-demented control cases to confirm the expected difference in neuroinflammation between the three groups
We investigated the level of ceramide using immunohistochemistry
Summary
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. The major neurodegenerative disorders, like Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal lobar dementia (FTLD), differ in the type of neurons that are affected and the nature of the accumulated proteins that propagate neurodegeneration. Numerous neurodegenerative diseases are associated with activated glial cells, but the inflammatory reaction is not distinguishable between the different diseases, despite the varying underlying causes [6,7,8]. The observed inflammatory glial response is presumed to be secondary to neuronal death or dysfunction, it is suggested that the activation of microglia and astrocytes contributes to the progression of the different neurodegenerative diseases. Understanding the underlying mechanisms involved in neuroinflammatory processes may reveal new molecular targets for future therapy [9,10,11]
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