Advertisement

Journal of Molecular Neuroscience

, Volume 20, Issue 3, pp 395–406 | Cite as

Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol

  • Suzana S. Petanceska
  • Steven DeRosa
  • Ali Sharma
  • Nichole Diaz
  • Karen Duff
  • Steven G. Tint
  • Lorenzo M. Refolo
  • Miguel Pappolla
Alzheimer’s Therapeutics: Lipid Lowering

Abstract

Apolipoprotein E (ApoE) influences the risk of late onset Alzheimer’s disease (AD) in an isoform-dependent manner, such that the presence of the apoE ε4 allele increases the risk of AD while the presence of the apoE ε2 allele appears to be protective. Although a number of ApoE functions are isoform dependent and may underlie the “risk factor” activity of AD, its ability to bind amyloid β peptides and influence their clearance and/or deposition has gained strong experimental support. Evidence suggests that in addition to genotype, increased ApoE transcription can contribute to AD risk. There is growing evidence in support of the hypothesis that disrupted cholesterol metabolism is an early risk factor for AD. Studies in animal models have shown that chronic changes in cholesterol metabolism associate with changes in brain Aβ accumulation, a process instrumental for establishing AD pathology. ApoE mediates cholesterol homeostasis in the body and is a major lipid carrier in brain. As such, its expression in the periphery and in brain changes in response to changes in cholesterol metabolism. Here, we used a transgenic mouse model of Alzheimer’s amyloidosis to examine whether the diet-induced or pharmacologically induced changes in plasma cholesterol that result in altered brain amyloidosis also affect ApoE content in liver and in brain. We found that chronic changes in total cholesterol in plasma lead to changes in ApoE mRNA levels in brain. We also found that cholesterol loading of primary glial cells increases cellular and secreted ApoE levels and that long-term treatment of astrocytes and microglia with statins leads to a decrease in the cellular and/or secreted ApoE. These observations suggest that disrupted cholesterol metabolism may increase the risk of developing AD in part due to the effect of cholesterol on brain ApoE expression.

Index Entries

Alzheimer’s disease ApoE cholesterol statin transgenic mice 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Artiga M. J., Bullido M. J., Frank A., Sastre I., Recuero M., Garcia M. A., et al. (1998) Risk for Alzheimer’s disease correlates with transcriptional activity of the APOE gene. Hum. Mol. Genet. 12, 1887–1892.CrossRefGoogle Scholar
  2. Bales K. R., Verina T., Cummins D. J., Du Y., Dodel R. C., Saura J., et al. (1999) Apolipoprotein E is essential for amyloid deposition in the APPV717F transgenic mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 96, 15,233–15,238.CrossRefGoogle Scholar
  3. Bjorkhem I., Meaney S., and Diczfalusy U. (2002) Oxysterols in human circulation: which role do they have? Curr. Opin. Lipidol. 13, 247–253.PubMedCrossRefGoogle Scholar
  4. Bullido M. J. and Valdivieso F. (2000) Apolipoprotein E gene polymorphisms in Alzheimer’s disease. Microsc. Res. Tech. 50, 261–267.PubMedCrossRefGoogle Scholar
  5. Buxbaum J. D., Cullen E. I., and Friedhoff L. T. (2002) Pharmacological concentrations of the HMGCoA reductase inhibitor lovastatin decrease the formation of the Alzheimer β-amyloid peptide in vitro and in patients. Front Biosci. 7, 50–59.CrossRefGoogle Scholar
  6. Canoll P. D., Petanceska S., Schlessinger J., and Musacchio J. M. (1996) Three forms of RPTP-beta are differentially expressed during gliogenesis in the developing rat brain and during glial cell differentiation in culture. J. Neurosci. Res. 44, 199–215.CrossRefGoogle Scholar
  7. Cole G. and Ard M. D. (2000) Influence of lipoproteins on microglial degradation of Alzheimer’s amyloid beta-protein. Microsc. Res. Tech. 15, 316–324.CrossRefGoogle Scholar
  8. Corder E. H., Saunders A. M., Strittmatter W. J., et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923.PubMedCrossRefGoogle Scholar
  9. Corder E. H., Saunders A. M., Risch N. J., et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 2, 180–184.CrossRefGoogle Scholar
  10. Driscoll D. M., Mazzone T., Matsushima T., and Getz G. S. (1990) Apoprotein E biosynthesis in the cholesterol-fed guinea pig. Arteriosclerosis 10, 31–39.PubMedGoogle Scholar
  11. Eckert G. P., Kirsch C., and Mueller, W. E. (2001) Differential effects of lovastatin treatment on brain cholesterol levels in normal and Apo-E deficient mice. Neuropharmacol. Neurotoxicol. 12, 883–887.Google Scholar
  12. Ehehalt R., Keller P., Haass C., Thiele C., and Simons K. (2003) Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 160, 113–123.PubMedCrossRefGoogle Scholar
  13. Fagan A. and Holtzman D. M. (2000) Astrocyte Lipoproteins, Effects of ApoE on neuronal function, and role of ApoE in amyloid β deposition in vivo. Microsc. Res. Tech. 50, 297–304.PubMedCrossRefGoogle Scholar
  14. Fagan A. M., Holtzman D. M., Munson G., Mathur T., Schneider D., Chang L. K., et al. (1999) Unique lipoproteins secreted by primary astrocytes from wild type, ApoE (-/-), and human ApoE transgenic mice. J. Biol. Chem. 274, 30,001–30,007.Google Scholar
  15. Fagan A. M., Watson M., Parsadanian M., Bales K. R., Paul S. M., and Holtzman D. M. (2002) Human and murine ApoE markedly alters Abeta metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 9, 305–318.PubMedCrossRefGoogle Scholar
  16. Fassbender K., Simons M., Bergmann C., Stroick M., Lutjohann D., Keller P., et al. (2001) 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. 98, 5856–5861.PubMedCrossRefGoogle Scholar
  17. Gandy S. and Petanceska S. (2000) Regulation of Alzheimer beta-amyloid precursor trafficking and metabolism. Biochim. Biophys. Acta 502, 44–52.Google Scholar
  18. Gueguen Y., Bertrand P., Ferrari L., Batt A. M., and Siest G. (2001) Control of apolipoprotein E secretion by 25-hydroxycholesterol and proinflammatory cytokines in the human astrocytoma cell line CCF-STTG1. Cell Biol. Toxicol. 17, 191–199.PubMedCrossRefGoogle Scholar
  19. Guo L., LaDu M. J., and Van Eldik L. J. (2002) ApoE down regulates pro-inflammatory responses induced by oligomeric Aβ in activated glia. Soc. Neurosci. Abstr. 883, 12.Google Scholar
  20. Hagberg J. M., Kenneth R. W., and Ferrell R. E. (2000) APOE gene and gene-environment effects on plasma lipoprotein-lipid levels. Physiol. Genomics 4, 101–108.PubMedGoogle Scholar
  21. Hamelin B. A. and Turgeon T. (1998) Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol. Sci. 19, 26–37.PubMedCrossRefGoogle Scholar
  22. Hartmann T. (2001) Cholesterol, A beta and Alzheimer’s disease. Trends Neurosci. 11(Suppl.), S45-S48.CrossRefGoogle Scholar
  23. Holcomb L., Gordon M. N., McGowan E., Yu X., Benkovic S., Jantzen P., et al. (1998) Accelerated Alzheimer’s type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin transgenes. Nat. Med. 4, 97–100.PubMedCrossRefGoogle Scholar
  24. Holtzman D. M. (2001) Role of apoe/Abeta interactions in the pathogenesis of Alzheimer’s disease and cerebral amyloid angiopathy. J. Mol. Neurosci. 17, 147–155.PubMedCrossRefGoogle Scholar
  25. Holtzman D. M., Bales K. R., Wu S., Bhat P., Parsadanian M., Fagan A. M., et al. (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer’s disease. J. Clin. Invest. 103, R15-R21.PubMedCrossRefGoogle Scholar
  26. Holtzman D. M., Fagan A. M., Mackey B., Tenkova T., Sartorius L., Paul S. M., et al. (2000a) Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann. Neurol. 47, 739–747.PubMedCrossRefGoogle Scholar
  27. Holtzman D. M., Bales K. R., Tenkova T., Fagan A. M., Parsadanian M., Sartorius L. J., et al. (2000b) Apolipoprotein-isoform dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 97, 2892–2897.PubMedCrossRefGoogle Scholar
  28. Honda A., Salen G., Nguyen L. B., Xu G., Tint G. S., Batta A. K., and Shefer S. (1998) Regulation of early cholesterol biosynthesis in rat liver: effects of sterols, bile acids, lovastatin, and BM 15.766 on 3-hydroxy-3-methylglutaryl coenzyme A synthase and acetoacetyl coenzyme A thiolase activities. Hepatology 27, 154–159.PubMedCrossRefGoogle Scholar
  29. Howland D. S., Trusko S. P., Savage M. J., et al. (1998) Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol. J. Biol. Chem. 273, 16,576–16,582.CrossRefGoogle Scholar
  30. Jarvik G. P., Austin M. A., Fabsitz R. R., Auwerx J., Reed T., Christian J. C., and Deeb S. (1994) Genetic influences on age related change in total cholesterol, low density lipoprotein cholesterol, triglyceride levels longitudinal apolipoprotein E genotype effects. Genet. Epidemiol. 11, 375–384.PubMedCrossRefGoogle Scholar
  31. Jarvik G. P., Wijsman E. M., Kukull W. A., Schellenberg G. D., Yu C., and Larson E. B. (1995) Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer’s disease: a case-control study. Neurology 45, 1092–1096.PubMedGoogle Scholar
  32. Jick H., Zornberg G. L., Jick S. S., Seshadri S., and Drachman D. A. (2000) Statins and the risk of dementia. Lancet 356, 1627–1631.PubMedCrossRefGoogle Scholar
  33. Jessen F., Rao M. L., von Bergmann K., and Heun R. (2000) Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J. Lipid. Res. 41, 195–198.PubMedGoogle Scholar
  34. Kivipelto M., Helkala E. L., Hanninen T., Laakso M. P., Hallikainen M., Alhainen K., et al. (2001) Midlife vascular risk factors and late life cognitive impairment: A population-based study. Neurology 56, 1683–1689.PubMedGoogle Scholar
  35. Kivipelto M., Helkala E. L., Laakso M. P., Hanninen T., Hallikainen M., Alhainen K., et al. (2002) Apolipoprotein E e4 allele, ellevated midlife total cholesterol level and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer’s disease. Ann. Intern. Med. 137, 149–155.PubMedGoogle Scholar
  36. Kojro E., Gimpi G., Lammich S., Marz W., and Fahrenzolc (2001) Low cholesterol stimulates the non-amyloidogenic pathway by its effect on the a-secretase ADAM 10. Proc. Natl. Acad. Sci. U.S.A. 98, 5815–5820.PubMedCrossRefGoogle Scholar
  37. Kolsch H., Lutjohann D., Ludwig M., Schulte A., Ptok U., Jessen F., et al. (2002) Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer’s disease. Mol. Psychiatry 7, 899–902.PubMedCrossRefGoogle Scholar
  38. Koudinov A. R., Berezov T. T., and Koudinova N. V. (2002) Cholesterol and Alzheimer’s disease: is there a link? Neurology 58, 1135.PubMedGoogle Scholar
  39. LaDu M. J., Shah J. A., Reardon C. A., Getz G. S., Bu G., Hu J., et al. (2001) Apolipoprotein E and apolipoprotein E receptors modlulate A beta-induced glial neuroinflammatory responses. Neurochem. Int. 39, 427–434.PubMedCrossRefGoogle Scholar
  40. Laffitte B. A., Repa J. J., Joseph S. B., Wilpitz D. C., Kast H. R., Mangelsdorf D. J., and Tontonoz P. (2001) LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci. U.S.A. 98, 507–512.PubMedCrossRefGoogle Scholar
  41. Lambert J. C., Mann D., Goumidi L., Harris J., Amouyel P., Iwatsubo T., et al. (2001) Effect of the APOE promoter polymorphisms on cerebral amyloid peptide deposition in Alzheimer’s disease. Lancet 357, 608–609.PubMedCrossRefGoogle Scholar
  42. Laskowitz D. T., Horsburgh K., and Roses A. D. (1998) Apolipoprotein E and the CNS response to injury. J. Cereb. Blood Flow Metab. 18, 465–471.PubMedCrossRefGoogle Scholar
  43. Laws S. M., Clarnette R. M., Taddei K., Martins G., Paton A., Hallmayer J., et al. (2002) APOE-epsilon4 and APOE-491A polymorphisms in individuals with subjective memory loss. Mol. Psychiatry 7, 768–775.PubMedCrossRefGoogle Scholar
  44. Levin-Allerhand J. A., Lominska C. E., and Smith J. D. (2002) Increased amyloid-levels in APPSWE transgenic mice treated chronically with a physiological high-fat high-cholesterol diet. J. Nutr. Health Aging 6, 315–319.PubMedGoogle Scholar
  45. Lynch J. R., Morgan D., Mance J., Mathew W. D., and Laskowitz D. T. (2001) Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J. Neuroimmunol. 114, 107–113.PubMedCrossRefGoogle Scholar
  46. Mazzone T., Basheeruddin K., and Poulos C. (1989) Regulation of macrophage apolipoprotein E gene expression by cholesterol. J. Lipid Res. 30, 1055–1064.PubMedGoogle Scholar
  47. Mazzone T., Gump H., Diller P., and Getz G. S. (1987) Macrophage free cholesterol content regulates apolipoprotein E synthesis. J. Biol. Chem. 262, 11,657–11,662.Google Scholar
  48. Mauch D. H., Nagler K., Schumacher S., Goritz C., Muller E. C., Otto A., and Pfrieger F. W. (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354–1357.PubMedCrossRefGoogle Scholar
  49. McGeer P. L. and McGeer E. G. (2001) Inflammation, autotoxicity and Alzheimer disease. Neurobiol. Aging 22, 799–809.PubMedCrossRefGoogle Scholar
  50. Meda L., Casatella M. A., Szendrei G. I., Otvos L. Jr., Baron P., Villalba M., et al. (1995) Activation of microglial cells by β-Amyloid protein and interferon-γ Nature 374, 647–650.PubMedCrossRefGoogle Scholar
  51. Naidu A., Xu Q., Catalano R., and Cordell B. (2002) Secretion of apolipoprotein E by brain glia requires protein prenylation and is suppressed by statins. Brain Res. 958, 100–111.PubMedCrossRefGoogle Scholar
  52. Naslund J., Haroutunian V., Mohs R., Davis K. L., Davies P., Greengard P., and Buxbaum J. D. (2000) Correlation between elevated levels of amyloid beta peptide in the brain and cognitive decline. JAMA 283, 1571–1577.PubMedCrossRefGoogle Scholar
  53. Neuroinflammation Working Group (2000) Inflammation and Alzheimer’s disease. Neurobiol. Aging 21, 383–421.CrossRefGoogle Scholar
  54. Notkola I. L., Sulkava R., Pekkanen J., Erkinjuntti T., Ehnholm C., Kivinen P., et al. (1998) Serum cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer’s disease. Neuroepidemiology 17, 14–20.PubMedCrossRefGoogle Scholar
  55. Ordovas J. M. and Mooser V. (2002) The ApoE locus and the pharmacogenetics of lipid response. Curr. Opin. Lipidol. 13, 113–117.PubMedCrossRefGoogle Scholar
  56. Papassotiropoulos A., Streffer J. R., Tsolaki M., et al. (2003) Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch. Neurol. 60, 29–35.PubMedCrossRefGoogle Scholar
  57. Parvathy S., Davies P., Haroutunian V., Purohit D. P., Davis K. L., Mohs R. C., et al. (2001) Correlation between Abeta x-40, Abeta x-42, and Abeta x-43 containing amyloid plaques and cognitive decline. Arch. Neurol. 58, 2025–2032.PubMedCrossRefGoogle Scholar
  58. Petanceska S. S., DeRosa S., Olm V., et al. (2002) Statin therapy for Alzheimer’s disease: will it work? J. Mol. Neurosci. 19, 155–161.PubMedCrossRefGoogle Scholar
  59. Petanceska S., Canoll P., and Devi L. A. (1996) Expression of rat cathepsin S in phagocytic cells. J. Biol. Chem. 271, 4403–4409.Google Scholar
  60. Prince M., Lovestone S., Cervilla J., Joels S., Powell J., Russ C., and Mann A. (2000) The association between ApoE and dementia does not seem to be mediated by vascular factors. Neurology 54, 397–402.PubMedGoogle Scholar
  61. Poirier J. (2000) Apolipoprotein E and Alzheimer’s disease. A role in amyloid catabolism. Ann. N. Y. Acad. Sci. 924, 81–90.PubMedCrossRefGoogle Scholar
  62. Puglielli L., Konopka G., Pack-Chung E., et al. (2001) Acylcoenzyme A: cholesterol acyl transferase modulates the generation of the amyloid beta-peptide. Nat. Cell. Biol. 3, 905–912.PubMedCrossRefGoogle Scholar
  63. Refolo L. M., Malester B., LaFrancois J., Bryant-Thomas T., Wang R., Tint G. S., et al. (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol. Dis. 7, 321–331.PubMedCrossRefGoogle Scholar
  64. Refolo L. M., Pappolla M. A., LaFrancois J., Malester B., Schmidt S. D., Thomas-Bryant T., et al. (2001) A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol. Dis. 8, 890–899.PubMedCrossRefGoogle Scholar
  65. Rockwood K., Kirkland S., Hogan D. B., MacKnight, Merry H., Verreault R., et al. (2002) Use of lipid lowering agents, indication bias, and the risk of dementia in community dwelling elderly people. Arch. Neurol. 59, 223–227.PubMedCrossRefGoogle Scholar
  66. Romas S. N., Tang M. X., Berglund L., and Mayeux R. (1999) APOE genotype, plasma lipids, lipoproteins, and AD in community elderly. Neurology 53, 517–521.PubMedGoogle Scholar
  67. Runz H., Rietdorf J., Tomic I., et al. (2002) Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J. Neurosci. 22, 1679–1689.PubMedGoogle Scholar
  68. Santillo M., Migliaro A., Mondola P., Laezza C., Damiano S., Stingo S., et al. (1999) Dietary and hypothyroid hypercholesterolemia induces hepatic apolipoprotein E expression in the rat: direct role of cholesterol. FEBS Lett. 463, 83–86.PubMedCrossRefGoogle Scholar
  69. Shie F. S., Jin L. W., Cook D. G., Leverenz J. B., and LeBoeuf R. C. (2002) Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice. Neuroreport 13, 455–459.PubMedCrossRefGoogle Scholar
  70. Simons M., Schwarzler F., Lutjohann D., von Bergmann C., Beyreuther K., Dichgans J., et al. (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26 week randomized, placebo-controlled, double-blind trial. Ann. Neurol. 52, 346–350.PubMedCrossRefGoogle Scholar
  71. Sparks D. L. (1996) Intraneuronal beta-amyloid immunoreactivity in the CNS. Neurobiol. Aging 17, 29,120–29,129.Google Scholar
  72. Sparks D. L., Liu H., Gross D. R., and Scheff S. W. (1995) Increased density of cortical apolipoprotein E immunoreactive neurons in rabbit brain after dietary administration of cholesterol. Neurosci. Lett. 187, 142–144.PubMedCrossRefGoogle Scholar
  73. Srivastava R. (1996a) Regulation of the apolipoprotein E by dietary lipids occurs by transcriptional and post-transcriptional mechanisms. Mol. Cell. Sci. 155, 153–162.Google Scholar
  74. Srivastava R. A., Bhasin N., and Srivastava N. (1996b) Apolipoprotein E gene expression in various tissues of mouse and regulation by estrogen. Biochem. Mol. Biol. Intern. 38, 91–101.Google Scholar
  75. Stone D. J., Rozovsky I., Morgan T. E., Anderson C. P., Hajian H., and Finch C. E. (1997) Astrocytes and microglia respond to estrogen with increased ApoE mRNA in vivo and in vitro. Exp. Neurol. 143, 313–318.PubMedCrossRefGoogle Scholar
  76. Wahrle S., Das P., Nyborg A. C., McLendon C., et al. (2002) Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 9, 11–23.PubMedCrossRefGoogle Scholar
  77. Wang J. C., Kwon J. M., and Shah P. (2000) Effect of APOE genotype and promoter polymorphism on risk of Alzheimer’s disease. Neurology 55, 1644–1649.PubMedGoogle Scholar
  78. Werb Z. and Chin J. R. (1983) Endotoxin suppresses expression of apolipoprotein E by mouse macrophages in vivo and in culture. A biochemical and genetic study. J. Biol. Chem. 258, 10,642–10,648.Google Scholar
  79. Wolozin B., Kellman W., Ruosseau P., Celesia G. G., and Siegel G. (2000) Decreased prevalence of Alzheimer’s disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch. Neurol. 57, 1439–1443.PubMedCrossRefGoogle Scholar
  80. Wong L. and Rubenstein D. (1997) The levels of apolipoprotein in hypercholesterolemic rat serum. J. Biochem. 56, 161–166.Google Scholar
  81. Yaffe K., Barrett-Connor E., Lin F., and Grady D. (2002) Serum lipoprotein levels, statin use, and cognitive function in older women. Arch. Neurol. 59, 378–384.PubMedCrossRefGoogle Scholar
  82. Yoshitake T., Kiyohara Y., Kato I., Ohmura T., Iwamoto H., Nakayama K., et al. (1995) Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology 6, 1161–1168.Google Scholar
  83. Xu Q., Li Y., Cyras C., Sanan D. A., and Cordell B. (2000) Isolation and characterization of apolipoproteins from murine microglia. Identification of a low density lipoprotein-like apolipoprotein J-rich but E-poor spherical particle. J. Biol. Chem. 275, 31,770–31,777.Google Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Suzana S. Petanceska
    • 1
    • 2
  • Steven DeRosa
    • 1
  • Ali Sharma
    • 1
  • Nichole Diaz
    • 1
  • Karen Duff
    • 1
    • 2
  • Steven G. Tint
    • 3
  • Lorenzo M. Refolo
    • 4
  • Miguel Pappolla
    • 5
  1. 1.Center for Dementia ResearchNathan Kline InstituteOrangeburg
  2. 2.Department of PsychiatryNYU Medical CenterNew York
  3. 3.University of Medicine and Dentistry of New Jersey
  4. 4.Institute for the Study of AgingNew York
  5. 5.University of South AlabamaMobile

Personalised recommendations