Increased Ceramide in Brains with Alzheimer's and Other Neurodegenerative Diseases

Abstract

Ceramide has been suggested to participate in the neuronal cell death that leads to Alzheimer’s disease (AD), but its role is not yet well-understood. We compared the levels of six ceramide subspecies, which differ in the length of their fatty acid moieties, in brains from patients who suffered from AD, other neuropathological disorders, or both. We found elevated levels of Cer16, Cer18, Cer20, and Cer24 in brains from patients with any of the tested neural defects. Moreover, ceramide levels were highest in patients with more than one neuropathologic abnormality. Interestingly, the range of values was higher among brains with neural defects than in controls, suggesting that the regulation of ceramide synthesis is normally under tight control, and that this tight control may be lost during neurodegeneration. These changes, however, did not alter the ratio between the tested ceramide species. To explore the mechanisms underlying this dysregulation, we evaluated the expression of four genes connected to ceramide metabolism: ASMase, NSMase 2, GALC, and UGCG. The patterns of gene expression were complex, but overall, ASMase, NSMase 2, and GALC were upregulated in specimens from patients with neuropathologic abnormalities in comparison with age-matched controls. Such findings suggest these genes as attractive candidates both for diagnostic purposes and for intervening in neurodegenerative processes.

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…Interestingly, only the inhibition of C99 production (by BI) resulted in an attenuation of sphingolipid synthesis and hydrolysis by sphingomyelinases (Fig 4E). These results indicate that it is the increase in C99 that causes the upregulation of sphingolipid metabolism, resulting in the previously described elevations in ceramide in AD (Filippov et al , 2012). However, they did not clarify why ceramide is particularly elevated in MAM and mitochondrial membranes.…”

“…Among these alterations, abnormal sphingolipid metabolism has been reported in AD tissues (van Echten‐Deckert & Walter, 2012). Specifically, there is an upregulation of de novo ceramide synthesis (Grimm et al , 2011) and an increase in the activity of sphingomyelinase (SMase), which catabolizes sphingomyelin (SM) into ceramide (Filippov et al , 2012). These alterations act synergistically to increase ceramide content in AD brains (Filippov et al , 2012).…”

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).…”

The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

“…При комбинации БА с другими патологиями уровень церамида оказывается самым высоким [82]. Наиболее определенные результаты были получены при изучении экспрессии генов, которые контролируют синтез, метаболизм и деградацию церамида в процессе развития БА.…”

“…Однако в мозге умерших пациентов, страдавших БА, обнаружена активация только кислой SMаse [81]. При анализе экспрессии генов, ответственных за синтез кислой SMаse и нейтральной SMаse2, было показано, что их активность резко повышается в мозге пациентов как с БА, так и с другими нейропатологиями [82].…”