Astroglial expression of ceramide in Alzheimer's disease brains: A role during neuronal apoptosis

Abstract

Accumulating evidences indicate that ceramide is closely involved in apoptotic cell death in neurodegenerative disorders and aging. We examined ceramide levels in the cerebrospinal fluid (CSF) or brain tissues from patients with neurodegenerative disorders and the mechanism of how intra- and extracellular ceramide was regulated during neuronal apoptosis. We screened the ceramide levels in the CSF of patients with neurodegenerative disorders, and found that ceramide was significantly increased in patients with Alzheimer's disease (AD) than in patients with age-matched amyotrophic lateral sclerosis (ALS) and other neurological controls. With immunohistochemistry in AD brains, ceramide was aberrantly expressed in astroglia in the frontal cortices, but not detected in ALS and control brains. To explore for the regulation of ceramide in astroglia in Alzheimer's disease brains, we examined the metabolism of ceramide during neuronal apoptosis. In retinoic acid (RA)-induced neuronal apoptosis, RA slightly increased de novo synthesis of ceramide, but interestingly, RA dramatically inhibited conversion of [14C] ceramide to glucosylceramide (GlcCer), suggesting that the increase of ceramide mass is mainly due to inhibition of the ceramide-metabolizing enzyme GlcCer synthase. In addition, a significant increase of the [14C] ceramide level in the culture medium was detected by chasing and turnover experiments without alteration of extracellular [14C] sphingomyelin levels. A 2.5-fold increase of ceramide mass in the supernatant was also detected after 48 h of treatment with RA. These results suggest a regulatory mechanism of intracellular ceramide through inhibition of GlcCer synthase and a possible role of ceramide as an extracellular/intercellular mediator for neuronal apoptosis. The increased ceramide level in the CSF from AD patients, which may be derived from astroglia, raises a possibility of neuronal apoptosis by the response to intercellular ceramide in AD.

Deregulation of sphingolipid metabolism in Alzheimer's disease

“…Two forms of Aβ are generally used for in vitro studies, fibrillar and oligomer. Several studies suggest that fibrillar Aβ induces primary neuron apoptosis via the activation of NSM (Ayasolla et al, 2004;Chen et al, 2006;Jana and Pahan, 2004;Lee et al, 2004;Satoi et al, 2005;Zeng et al, 2005). However, our data using postmortem AD brain revealed that ASM, not NSM, activity was elevated.…”

“…In vitro, Aβ has been shown to induce apoptosis via the sphingomyelin/ceramide pathway in various brain cells, including human and rat primary neurons (Jana and Pahan, 2004;Ju et al, 2005;Malaplate-Armand et al, 2006), rat oligodendrocytes (Cheng et al, 2003;Lee et al, 2004;Malaplate-Armand et al, 2006;Zeng et al, 2005), rat astrocytes and glial cells (Ayasolla et al, 2004), and murine neuroblastoma cells (Satoi et al, 2005). Calcium-dependent phospholipase A (cPLA) (Malaplate-Armand et al, 2006), inducible nitric oxide synthase (iNOS) (Ayasolla et al, 2004;Zeng et al, 2005), the p75 neurotrophin receptor (p75NTR) (Costantini et al, 2005), and NADPH oxidase (Jana and Pahan, 2004) have each been shown to be involved in the Aβ-related activation of the sphingomyelin/ceramide pathway.…”

“…For example, the total phospholipid and sulfatide content in AD was decreased as compared to normal (Cheng et al, 2003;Gottfries et al, 1996;Han et al, 2002;Pettegrew et al, 2001;Soderberg et al, 1992), while the ceramide and cholesterol levels were elevated (Cutler et al, 2004;Han et al, 2002). Satoi et al found that the ceramide levels in the cerebrospinal fluid (CSF) also were increased in patients with AD (Satoi et al, 2005), and we recently reported that the level and activity of acid ceramidase (AC) was elevated as well, perhaps in response to the elevated ceramide (Huang et al, 2004). Herein we investigated the levels of sphingomyelin and several other sphingolipid metabolites in the brains of AD patients, as well as the levels and activities of several lipid-related enzymes.…”

Serum sphingomyelins and ceramides are early predictors of memory impairment

“…The conflicting results could be due to the stage of the disease process studied. One CSF study reported higher ceramide levels in moderate versus mild or severe AD [28], while another examining brain tissue reported that the gene expression patterns of enzymes participating in the sphingolipid metabolism pathway varied by AD severity [18]. Similarly, we found serum SM and ceramides varied by time to onset of memory impairment, such that levels were higher pre-symptomatically but lower at the time of impairment.…”

“…Limited clinical research has examined the role of SM and ceramides in AD pathogenesis. Post-mortem studies and the one CSF study suggest AD cases have higher levels of SM and/or ceramides [7,13,25,26,28]. Importantly, levels also vary by disease severity [7,13,28], suggesting the possible use of these lipids as biomarkers of AD progression.…”