Pivotal Role for Acidic Sphingomyelinase in Cerebral Ischemia-Induced Ceramide and Cytokine Production, and Neuronal Apoptosis

Yu, Zhiming; Nikolova‐Karakashian, Mariana; Zhou, Daohong; Cheng, Guanjun; Schuchman, Edward H.; Mattson, Mark P.

doi:10.1385/jmn:15:2:85

Cited by 194 publications

(156 citation statements)

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“…5A). When taken together with previous studies showing that ceramide can induce apoptosis of neurons (14), these findings suggest a critical and essential role for perturbed sphingolipid metabolism, and ceramide production in the neurotoxic actions of A␤.…”

Section: Membrane-associated Oxidative Stress and Ceramide Productionsupporting

confidence: 68%

“…High levels of free cholesterol can be toxic to cells as demonstrated by the ability of inhibitors of ACAT (an enzyme that converts free cholesterol to cholesterol esters) to induce apoptosis (31,50) and by the ability of statins to protect neurons against ischemic͞oxidative injury (51,52). In addition to having direct adverse effects in neurons, the increased levels of ceramides in the brain during aging may also promote inflammatory processes (14). The involvement of perturbed sphingomyelin and cholesterol metabolism in the neurotoxic actions of A␤, and their strong associations with the pathogenesis of AD, suggests a novel approach for therapeutic intervention downstream of A␤.…”

Section: Discussionmentioning

confidence: 99%

“…The average age of patients was 79.8 Ϯ 2.0 (range 54-94). Average postmortem interval for all AD patients was 5.6 Ϯ 0.6 h (range [2][3][4][5][6][7][8][9][10][11][12][13][14]. No clinical stage-associated difference in average postmortem interval was present.…”

Section: Methodsmentioning

confidence: 99%

“…Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a form of programmed cell death called apoptosis (13). Ceramides have been implicated in the pathological death of neurons that occurs in ischemic stroke (14) and Parkinson's disease (15). In the present study, we document significant increases in levels of membrane-associated oxidative stress, long-chain ceramides, and free cholesterol in brain cells during normal aging in mice, in AD patients, and in neurons exposed to A␤.…”

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confidence: 99%

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Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Cutler

Kelly

Storie

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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989

854

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Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid ␤-peptide (A␤) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to A␤ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to A␤ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with ␣-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by A␤. Our findings suggest a sequence of events in the pathogenesis of AD in which A␤ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.amyloid ͉ apoptosis ͉ hippocampus ͉ lipid peroxidation ͉ sphingomyelin C hanges that occur in the brain during aging increase the risk of Alzheimer's disease (AD), a disorder involving the progressive deposition of amyloid ␤-peptide (A␤) and associated degeneration of neurons in brain regions involved in learning and memory (1). Two factors that are believed to contribute to neuronal dysfunction and degeneration in AD are increased oxidative stress and increased production of neurotoxic forms of A␤ (2). Alterations in lipid metabolism may also play roles in AD because the risk of AD is affected by inheritance of different isoforms of apolipoprotein E (3), changes in cholesterol metabolism can affect A␤ production in cell culture and in vivo (4-6), and drugs that lower cholesterol levels may reduce the risk of AD (7,8). However, a direct link between alterations in the metabolism of cholesterol and other membrane lipids in AD has not been established, and it is not known whether and how such lipid alterations might lead to neuronal dysfunction and death.Membrane microdomains that are rich in cholesterol and sphingolipids play important roles in various cellular signaling pathways (9, 10). Sphingomyelin is a major source of ceramides, lipid mediators that are generated when sphingomyelin is cleaved by sphingomyelinases, enzymes activated by inflammatory cytokines (11) and oxidative stress (12). Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a form of programmed cell death called apoptosis (13). Ceramides have been implicated in the pathological death of neurons that occurs in ischemic stroke (14) and Parkinson's disease (15). In the present study, we document significant increases in levels of m...

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Section: Membrane-associated Oxidative Stress and Ceramide Productionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease

Cutler

Kelly

Storie

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

989

854

View full text Add to dashboard Cite

show abstract

“…Ceramide may be a key mediator of some radiation-and chemotherapeutic responses of tumors (Santana et al, 1996;Morita et al, 2000;Pena et al, 2000;Paris et al, 2001;Garcia-Barros et al, 2003), the infectious program of some bacteria and viruses (Grassme´et al, 1997Jan et al, 2000;Esen et al, 2001), the pathogenesis of hereditary sensory neuropathy type I (Bejaoui et al, 2001;Dawkins et al, 2001), heat damage, UVA light and ischemia-reperfusion injury (Yu et al, 2000;Zhang et al, 2001;Chung et al, 2003) -to list a few examples. In some settings, ceramide is also required for induction of apoptosis by CD95 (Cifone et al, 1994;Gulbins et al, 1995;Cremesti et al, 2001;) and the TNF receptor (Schu¨tze et al, 1992), and during the physiological process of oocyte atresia (Morita et al, 2000).…”

Section: Introductionmentioning

confidence: 99%