Deregulation of sphingolipid metabolism in Alzheimer's disease

Abstract

Abnormal sphingolipid metabolism has been previously reported in Alzheimer's disease (AD). To extend these findings, several sphingolipids and sphingolipid hydrolases were analyzed in brain samples from AD patients and age-matched normal individuals. We found a pattern of elevated acid sphingomyelinase (ASM) and acid ceramidase (AC) expression in AD, leading to a reduction in sphingomyelin and elevation of ceramide. More sphingosine also was found in the AD brains, although sphingosine-1-phosphate (S1P) levels were reduced. Notably, significant correlations were observed between the brain ASM and S1P levels and the levels of amyloid beta peptide (Aβ) and phosphorylated tau protein. Based on these findings, neuronal cell cultures were treated with Aβ oligomers, which were found to activate ASM, increase ceramide, and induce apoptosis. Pretreatment of the neurons with purified, recombinant AC prevented the cells from undergoing Aβ-induced apoptosis. We propose that ASM activation is an important pathological event leading to AD, perhaps due to Aβ deposition. The downstream consequences of ASM activation are elevated ceramide, activation of ceramidases, and production of sphingosine. The reduced levels of S1P in the AD brain, together with elevated ceramide, likely contribute to the disease pathogenesis.

Lipid metabolism in Alzheimer’s disease

“…The role of sphingolipids in AD has been studied since the last two decades. Several reports, including post-mortem studies, have shown that ceramide levels are elevated in cortical regions of the AD brain [109][110][111] and CSF [112] and this increase is accompanied by decreased sulfatide levels in the same regions. Given that ceramide results from sulfatide degradation, these results indicate decreased sulfatide metabolism in the AD brain.…”

“…Recent studies showed that the levels of acid sphingomyelinase, the hydrolysis of sphingomyelins, and the generation of ceramide are positively correlated with hyperphosphorylated tau and Aβ levels in the AD brain [111] , suggesting that ceramide generated by acid sphingomyelinase mediates the toxic effects of hyperphosphorylated tau and Aβ. S1P accumulation promotes tau hyperphosphorylation by increasing calpain and CDK5, which induces cell-cycle reactivation and neurotoxicity [126] .…”

“…Recently, a study showed that hippocampal ceramide levels are decreased [113] . In [110][111][112][113][114] , and ceramide in turn influences Aβ production by stabilizing β-secretase and promoting the amyloidogenic pathway of APP processing [115,116] . …”

“…There is a large and growing number of reports covering the role of sphingolipid metabolites, especially ceramide and sphingosine-1-phosphate (S1P) in neuronal signaling and function. This important aspect has recently been extensively reviewed by Colombaioni and GarciaGil [125] .Recent studies showed that the levels of acid sphingomyelinase, the hydrolysis of sphingomyelins, and the generation of ceramide are positively correlated with hyperphosphorylated tau and Aβ levels in the AD brain [111] , suggesting that ceramide generated by acid sphingomyelinase mediates the toxic effects of hyperphosphorylated tau and Aβ. S1P accumulation promotes tau hyperphosphorylation by increasing calpain and CDK5, which induces cell-cycle reactivation and neurotoxicity [126] .…”

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

“…Exogeneous Cer has previously been shown to increase the half-life of BACE1 and promote the production of Aβ in human neuroglioma cells and Chinese hamster ovary cells (Puglielli et al, 2003). In addition, the level of Cer was observed to increase in different regions of the brain in both AD patients (Han et al, 2002;He et al, 2010;Chan et al, 2012;Filippov et al, 2012) and mouse model of AD (Barrier et al, 2010). In PS1/PS2 deficiency mouse embryonic fibroblast cells, increased level of SM was observed with reduction in the activity of neutral sphingomyelinase (nSMase).…”