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PMID: 14970312 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 7 ·2004-02-17 ·Pages 2070-5

Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP

Abstract

Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid beta-peptide (Abeta) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to Abeta 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 Abeta induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with alpha-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by Abeta. Our findings suggest a sequence of events in the pathogenesis of AD in which Abeta induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.

MeSH Terms
Aging/metabolism Alzheimer Disease/metabolism,pathology Amyloid beta-Peptides/metabolism,pharmacology Animals Brain/cytology,metabolism,pathology Cell Death/drug effects Cell Membrane/metabolism Cells, Cultured Ceramides/biosynthesis,metabolism Cholesterol/metabolism Humans Lipid Peroxidation Mice Neurons/drug effects,metabolism,pathology Oxidative Stress Sphingolipids/biosynthesis,metabolism
Chemicals
Amyloid beta-Peptides Ceramides Sphingolipids Cholesterol
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Cutler Roy G
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Kelly Jeremiah
Storie Kristin
Pedersen Ward A
Tammara Anita
Hatanpaa Kimmo
Troncoso Juan C
Mattson Mark P
References (52)
52 references, click to expand
  1. Immunohistochemical investigation of the brain of aged dogs. I. Detection of neurofibrillary tangles and of 4-hydroxynonenal protein, an oxidative damage product, in senile plaques.
    Amyloid. 2001 Mar;8(1):11-21 PMID: 11293821
  2. Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation.
    Eur J Neurosci. 2001 Jun;13(11):2037-46 PMID: 11422444
  3. Inhibition of neutral sphingomyelinase activation and ceramide formation by glutathione in hypoxic PC12 cell death.
    J Neurochem. 1999 Aug;73(2):675-83 PMID: 10428064
  4. Cytokine response modifier A (CrmA) inhibits ceramide formation in response to tumor necrosis factor (TNF)-alpha: CrmA and Bcl-2 target distinct components in the apoptotic pathway.
    J Exp Med. 1997 Feb 3;185(3):481-90 PMID: 9053448
  5. Changes in free and esterified cholesterol: hallmarks of acute renal tubular injury and acquired cytoresistance.
    Am J Pathol. 2000 Sep;157(3):1007-16 PMID: 10980139
  6. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases.
    Neurobiol Aging. 2002 Sep-Oct;23(5):795-807 PMID: 12392783
  7. Functions of lipid rafts in biological membranes.
    Annu Rev Cell Dev Biol. 1998;14:111-36 PMID: 9891780
  8. Statin inhibits leukocyte-endothelial interaction and prevents neuronal death induced by ischemia-reperfusion injury in the rat retina.
    Arch Ophthalmol. 2002 Dec;120(12):1707-13 PMID: 12470146
  9. Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid beta-peptide toxicity.
    J Neurochem. 1996 Feb;66(2):869-72 PMID: 8592164
  10. Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis.
    Ann Neurol. 2002 Oct;52(4):448-57 PMID: 12325074
  11. Specificity of inhibitors of serine palmitoyltransferase (SPT), a key enzyme in sphingolipid biosynthesis, in intact cells. A novel evaluation system using an SPT-defective mammalian cell mutant.
    Biochem Pharmacol. 2000 May 15;59(10):1211-6 PMID: 10736421
  12. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts.
    J Cell Biol. 2003 Jan 6;160(1):113-23 PMID: 12515826
  13. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide.
    Nat Cell Biol. 2001 Oct;3(10):905-12 PMID: 11584272
  14. Plasma membrane cholesterol controls the cytotoxicity of Alzheimer's disease AbetaP (1-40) and (1-42) peptides.
    FASEB J. 2002 Oct;16(12):1526-36 PMID: 12374775
  15. Molecular analysis of acid ceramidase deficiency in patients with Farber disease.
    Hum Mutat. 2001 Mar;17(3):199-209 PMID: 11241842
  16. Involvement of sphingomyelinases in TNF signaling pathways.
    Chem Phys Lipids. 1999 Nov;102(1-2):157-66 PMID: 11001570
  17. Pivotal role for acidic sphingomyelinase in cerebral ischemia-induced ceramide and cytokine production, and neuronal apoptosis.
    J Mol Neurosci. 2000 Oct;15(2):85-97 PMID: 11220788
  18. Oxidative alterations in Alzheimer's disease.
    Brain Pathol. 1999 Jan;9(1):133-46 PMID: 9989456
  19. Amyloid beta-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation.
    J Neurosci. 1997 Feb 1;17(3):1046-54 PMID: 8994059
  20. Alzheimer's disease: the cholesterol connection.
    Nat Neurosci. 2003 Apr;6(4):345-51 PMID: 12658281
  21. Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains.
    Neurobiol Dis. 2002 Feb;9(1):11-23 PMID: 11848681
  22. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity.
    Trends Neurosci. 1998 Feb;21(2):53-7 PMID: 9498297
  23. Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease.
    Neurobiol Aging. 1997 Sep-Oct;18(5):457-61 PMID: 9390770
  24. Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells.
    J Neurosci. 2002 Mar 1;22(5):1679-89 PMID: 11880497
  25. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis.
    J Neurosci. 1997 Jul 1;17(13):5089-100 PMID: 9185546
  26. A mechanism for the neuroprotective effect of apolipoprotein E: isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal.
    J Neurochem. 2000 Apr;74(4):1426-33 PMID: 10737598
  27. Cytotoxic cholesterol is generated by the hydrolysis of cytoplasmic cholesteryl ester and transported to the plasma membrane.
    Atherosclerosis. 1999 Oct;146(2):309-19 PMID: 10532697
  28. Ceramide induces apoptosis in PC12 cells.
    FEBS Lett. 1997 Jan 20;401(2-3):148-52 PMID: 9013876
  29. Persistence of increased cholesteryl ester in human skin fibroblasts is caused by residual exogenous sphingomyelinase and is reversed by phospholipid liposomes.
    Biochim Biophys Acta. 1992 Dec 2;1165(2):153-9 PMID: 1450209
  30. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors.
    Arch Neurol. 2000 Oct;57(10):1439-43 PMID: 11030795
  31. Effects of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death.
    Arterioscler Thromb Vasc Biol. 1998 Mar;18(3):423-31 PMID: 9514411
  32. Apoptosis in neurodegenerative disorders.
    Nat Rev Mol Cell Biol. 2000 Nov;1(2):120-9 PMID: 11253364
  33. Effects of supplementing with vitamin E on the uptake of low density lipoprotein and the stimulation of cholesteryl ester formation in macrophages.
    Atherosclerosis. 1994 Sep 30;110(1):77-86 PMID: 7857373
  34. [Effect of ganglioside GM1 on the metabolism of Alzheimer amyloid beta-protein precursor].
    Zhonghua Yi Xue Za Zhi. 1998 Mar;78(3):179-82 PMID: 10923524
  35. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin.
    Biochem Biophys Res Commun. 1995 Jun 15;211(2):396-403 PMID: 7794249
  36. Ceramide induces apoptosis in cultured mesencephalic neurons.
    J Neurochem. 1996 Feb;66(2):733-9 PMID: 8592146
  37. Epidemiology and pathophysiology of Alzheimer's disease.
    Clin Cornerstone. 2001;3(4):15-26 PMID: 11432119
  38. Role of ceramide in neuronal cell death and differentiation.
    J Neurotrauma. 2000 Oct;17(10):891-8 PMID: 11063055
  39. Iron/ascorbate-induced lipid peroxidation changes membrane fluidity and muscarinic cholinergic receptor binding in rat frontal cortex.
    Neurochem Int. 1993 Nov;23(5):479-84 PMID: 8251930
  40. Oxidative stress leads to cholesterol accumulation in vascular smooth muscle cells.
    Free Radic Biol Med. 1999 Jul;27(1-2):134-45 PMID: 10443930
  41. Caspase-dependent ceramide production in Fas- and HLA class I-mediated peripheral T cell apoptosis.
    J Biol Chem. 1998 Feb 27;273(9):5060-6 PMID: 9478956
  42. Application of exogenous ceramide to cultured rat spinal motoneurons promotes survival or death by regulation of apoptosis depending on its concentrations.
    J Neurosci Res. 1998 Nov 15;54(4):475-85 PMID: 9822158
  43. Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death.
    J Neurosci. 1995 Sep;15(9):6239-49 PMID: 7666206
  44. p53-dependent ceramide response to genotoxic stress.
    J Clin Invest. 1998 Jul 15;102(2):329-39 PMID: 9664074
  45. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives.
    Physiol Rev. 1997 Oct;77(4):1081-132 PMID: 9354812
  46. prICE: a downstream target for ceramide-induced apoptosis and for the inhibitory action of Bcl-2.
    Biochem J. 1996 May 15;316 ( Pt 1):25-8 PMID: 8645213
  47. Cholesterol depletion with physiological concentrations of a statin decreases the formation of the Alzheimer amyloid Abeta peptide.
    J Alzheimers Dis. 2001 Apr;3(2):221-229 PMID: 12214063
  48. Signaling in and regulation of ionizing radiation-induced apoptosis in endothelial cells.
    Recent Prog Horm Res. 1998;53:85-92; discussion 93 PMID: 9769704
  49. Lipid rafts in neuronal signaling and function.
    Trends Neurosci. 2002 Aug;25(8):412-7 PMID: 12127758
  50. The role of sphingomyelin cycle metabolites in transduction of signals of cell proliferation, differentiation and death.
    Membr Cell Biol. 2000;13(2):303-20 PMID: 10779176
  51. Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo.
    Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61 PMID: 11296263
  52. Apolipoprotein E4: an allele associated with many diseases.
    Ann Med. 2000 Mar;32(2):118-27 PMID: 10766403
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0305799101
Published
2004-02-17
Epub
2004-00-15
Pages
2070-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC357053
Subset
IM
Grants
NIA NIH HHS · AG05146 · United States
NIA NIH HHS · P50 AG005146 · United States
NIA NIH HHS · 1RO3 AG19493-0 · United States
NIA NIH HHS · P30 AG10161 · United States
NIA NIH HHS · P30 AG010161 · United States
External Links
PubMed source DOI: 10.1073/pnas.0305799101 PMC Full Text View journal details
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