Relationship to Alzheimers Disease

Alzheimer's disease is neuropathologically defined by the presence in the brain of two features, amyloid deposits of the Ap peptide and neurofibrillary tangles (NFT) of the tau protein. The risk of AD is increased by inheritance of the e4 allele of apoE, and decreased by inheritance of the e2 allele of apoE.1 Apolipoprotein E e4 is associated with increased amy-loid,23,77,78 but not increased NFTs.78 Thus, it has been postulated that apoE4 is involved either in increased deposition of Ap, or decreased clearance of Ap.

The putative apoE-Ap interactions have been supported by several different studies. Apolipoprotein E binds Ap in vitro, whether apoE is delipidated79 or bound to lipopro-teins.80 Apolipoprotein E can also promote Ap aggregation in vitro;81-83 this model is supported in vivo in mouse models of amyloidogenesis showing that apoE knockout mice have considerably delayed Ap deposition.84 Ap clearance can be promoted by interactions with the lipoprotein receptors LRP,85,86 gp330,87,88 and scavenger receptor A-I.89,90 The apoE isoforms may differentially affect these various clearance mechanisms. Apolipoprotein E may also affect Ap levels by altering the interaction between the amyloid precursor protein and LRP.91,92

The studies of apoE as a genetic risk factor in AD promoted analysis of apoE receptor genes as candidate risk factors for AD. No consistent linkage was found between AD and polymorphisms in the LDL receptor gene,93 the VLDL receptor gene,28,93-95 and a polymorphism in the 3' untranslated region of LRP.93,96,97 However, a polymorphism in exon 3 of LRP has been linked to AD in several studies.98-101 While this polymorphism does not alter the amino acid sequence of LRP, it has sparked further interest in analysis of other regions of LRP and other ligands of LRP as potential genetic risk factors.

In summary, recent investigations have revealed a complex family of exchangeable apolipoproteins which can be synthesized by resident CNS cells and contribute to the classes of lipoproteins found in the brain. These lipoproteins form a unique class of particles, distinct from that seen in the periphery, which appears to be capable of mediating both lipid removal and delivery. The CNS lipoproteins have available a wide array of at least five potential receptors, each with a unique cellular and regional distribution and with multiple splice forms and soluble forms. This much diversity no doubt underlies a similar diversity in cellular function which we are only beginning to understand. Efforts in this direction are progressing rapidly, however, due in large part to the identification of members of this family of ligands and receptors as candidate genes in Alzheimer's disease.

References

1. Strittmatter W, Roses A. Apolipoprotein E and Alzheimer's disease. Ann Rev Neurosci 1996; 19:53-77.

2. Poirier J, Hess M, May PC et al. Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Mol Brain Res 1991; 11:97-106.

3. Masliah E, Mallory M, Ge N et al. Neurodegeneration in the central nervous system of apoE-deficient mice. Exp Neurol 1995; 136:107-122.

4. Handelmann GE, Boyles JK, Weisgraber KH et al. Effects of apolipoprotein E, ß-very low density lipoproteins, and cholesterol on the extensions of neurites by rabbit dorsal root ganglion neurons in vitro. J Lipid Res 1992; 33:1677-1688.

5. Pitas RE, Boyles JK, Lee SH et al. Lipoproteins and their receptors in the central nervous system. J Biol Chem 1987; 262:14352-14360.

6. Borghini I, Barja F, Pometta D et al. Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid. Biochim Biophys Acta 1995; 1255:192-200.

7. LaDu MJ, Gilligan SM, Lukens JR et al. Nascent astrocyte particles differ from lipoproteins in CSF. J Neurochem 1998; 70:2070-2081.

8. Guyton JR, Miller SE, Martin ME et al. Novel large apolipoprotein E-containing lipoproteins of density 1.006-1.060 g/ml in human cerebrospinal fluid. J Neurochem 1998; 70:1235-1240.

9. Koudinov AR, Koudinova NV, Kumar A et al. Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: Association with high density lipoproteins. Biochem Biophys Res Commun 1996; 223:592-597.

10. Roheim PS, Carey M, Forte T et al. Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci USA 1979; 76:4646-4649.

11. Boyles JK, Pitas RE, Wilson E et al. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest 1985; 76:1501-1513.

12. Pitas RE, Boyles JK, Lee SH et al. Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins. Biochim Biophys Acta 1987; 917:148-161.

13. Nakai M, Kawamata T, Taniguchi T et al. Expression of apolipoprotein E mRNA in rat microglia. Neurosci Lett 1996; 211:41-44.

14. Stone DJ, Rozovsky I, Morgan TE et al. Astrocytes and microglia respond to estrogen with increased apoE mRNA in vivo and in vitro. Exp Neurol 1997; 143:313-318.

15. Linton MF, Gish R, Hubl ST et al. Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation. J Clin Invest 1991; 88:270-281.

16. Aronow BJ, Lund SD, Brown TL et al. Apolipoprotein J expression at fluid-tissue interfaces: Potential role in barrier cytoprotection. Proc Natl Acad Sci USA 1993; 90:725-729.

17. Provost PR, Villeneuve L, Weech PK et al. Localization of the major sites of rabbit apolipoprotein D gene transcription by in situ hybridization. J Lipid Res 1991; 32:1959-1970.

18. Page K, Hollister RD, Hyman BT. Dissociation of apolipoprotein and apolipoprotein receptor response to lesion in the rat brain: An in situ hybridization study. Neurosci 1998; 85:1161-1171.

19. Ji Z-S, Brecht WJ, Miranda RD et al. Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein E-enriched remnant lipoproteins by cultured cells. J Biol Chem 1993; 268:10160-10167.

20. Lilly-Stauderman M, Brown TL, Balasubramaniam A et al. Heparin releases newly synthesized cell surface associated apolipoprotein E from HepG2 cells. J Lipid Res 1993; 34:190-200.

21. Ji Z-S, Fazio S, Lee Y-L et al. Secretion-capture role for apolipoprotein E in remnant lipo-protein metabolism involving cell surface heparan sulfate proteoglycans. J Biol Chem 1994; 269:2764-2772.

22. Weisgraber KH. Apolipoprotein E: Structure-function relationships. Adv Prot Chem 1994; 45:249-302.

23. Rebeck GW, Reiter JS, Strickland DK et al. Apolipoprotein E in sporadic Alzheimer's disease: Allelic variation and receptor interactions. Neuron 1993; 11:575-580.

24. Swanson LW, Simmons DM, Hofmann SL et al. Localization of mRNA for low density lipoprotein receptor and a cholesterol synthetic enzyme in rabbit nervous system by in situ hybridization. Proc Natl Acad Sci USA 1988; 85:9821-9825.

25. Poirier J, Baccichet A, Dea D et al. Cholesterol synthesis and lipoprotein reuptake during synaptic remodeling in hippocampus in adult rats. Neurosci. 1993; 55:81-90.

26. Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. TINS 1994; 17:525-530.

27. Christie RH, Chung H, Rebeck GW et al. Expression of the very low density lipoprotein receptor (VLDL-r), an apolipoprotein E receptor, in the central nervous system and in Alzheimer disease. J Neuropath Exp Neurol 1996; 55:491-498.

28. Okuizumi K, Onodera O, Namba Y et al. Genetic association of the very low density lipoprotein (VLDL) receptor with sporadic Alzheimer's disease. Nature Genet 1995; 11:207-209.

29. Kim D-H, Iijima H, Goto K et al. Human apolipoprotein E receptor 2. J Biol Chem 1996; 271:8373-8380.

30. Clatworthy AE, Stockinger W, Christie RH et al. Expression and alternate splicing of apoE receptor 2 in brain. Neurosci 1998; in press.

31. Wolf BB, Lopes MBS, VandenBerg SR et al. Characterization and immunohistochemical localization of a2-macroglobulin receptor (low-density lipoprotein receptor-related protein) in human brain. Am J Path 1992; 141:37-42.

32. Moestrup SK, Gliemann J, Pallensen G. Distribution of the a2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues. Cell Tissue Res 1992; 269:375-382.

33. Lopes MBS, Bogaev CA, Gonias SL et al. Expression of a2-macroglobulin receptor/low density lipoprotein receptor-related protein is increased in reactive and neoplastic glial cells. FEBS Lett 1994; 338:301-305.

34. Kounnas MZ, Loukinova EB, Stefansson S et al. Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin. submitted 1995.

35. Zheng G, Bachinsky DR, Stamenkovic I et al. Organ distribution in rats of two members of the low-density lipoprotein receptor gene family, gp330 and LRP/a2MR, and the receptor-associated protein (RAP). J Histochem Cytochem 1994; 42:531-542.

36. Medh JD, Fry GL, Bowen SL et al. The 39-kDa receptor-associated protein modulates lipoprotein metabolism by binding to LDL receptors. J Biol Chem 1995; 270:536-540.

37. Battey FD, Gafvels ME, FitzGerald DJ et al. The 39 kDa receptor-associated protein regulates ligand binding by the very low density lipoprotein receptor. J Biol Chem 1994; 269:23268-23273.

38. Novak S, Hiesberger T, Schneider WJ et al. A new low density lipoprotein receptor homologue with 8 ligand binding repeats in brain of chicken and mouse. J Biol Chem 1996; 271:11732-11736.

39. Herz J, Goldstein JL, Strickland DK et al. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/a2-macroglobulin receptor. J Biol Chem 1991; 266:21232-21238.

40. Kounnas MZ, Argraves WS, Strickland DK. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, a2-macroglobulin receptor and glucoprotein 330. J Biol Chem 1992; 267:21162-21166.

41. Bu G, Geuze HJ, Strous GJ et al. 39 kDa receptor-associated protein is an ER resident protein and molecular chaperone for LDL receptor-related protein. EMBO J 1995; 14:2269-2280.

42. Willnow TE, Rohlmann A, Horton J et al. RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. EMBO J 1996; 15:3632-3639.

43. Rebeck GW, Harr SD, Strickland DK et al. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the a2-macroglobulin receptor/low-den-sity-lipoprotein receptor-related protein. Ann Neurol 1995; 37:211-217.

44. Bu G, Rennke S. Receptor-associated protein is a folding chaperone for low density lipoprotein receptor-related protein. J Biol Chem 1996; 271:22218-22224.

45. Williams SE, Ashcom JD, Argraves WS et al. A novel mechanism for controlling the activity of a2-macroglobulin receptor/low density lipoprotein receptor-related protein. J Biol Chem 1992; 267:9035-9040.

46. Moestrup SK, Holtet TL, Etzerodt M et al. a2-macroglobulin-proteinase complexes, plasminogen activator inhibitor type-1-plasminogen activator complexes, and receptor associated protein bind to a region of the a2-macroglobulin receptor containing a cluster of eight complement-type repeats. J Biol Chem 1993; 268:13691-13696.

47. Willnow TE, Orth K, Herz J. Molecular dissection of ligand binding sites on the low density lipoprotein receptor-related protein. J Biol Chem 1994; 269:15827-15832.

48. Horn IR, van der Berg BMM, van der Meijden PZ et al. Molecular analysis of ligand binding to the second cluster of complement-type repeats of the low density lipoprotein receptor-related protein. J Biol Chem 1997; 272:13608-13613.

49. Orlando RA, Exner M, Czekay R-P et al. Identification of the second cluster of ligand-binding repeats in megalin as a site for receptor-ligand interactions. Proc Natl Acad Sci USA 1997; 94:2368-2373.

50. Heegaard CW, Simonsen ACW, Oka K et al. Very low density lipoprotein receptor binds and mediates endocytosis of urokinase-type plasminogen activator-type-1 plasminogen activator inhibitor complex. J Biol Chem 1995; 270:20855-20861.

51. Takahashi S, Suzuki J, Kohno M et al. Enhancement of the binding of triglyceride-rich lipoproteins to the very low density lipoprotein receptor by apolipoprotein E and lipoprotein lipase. J Biol Chem 1995; 270:15747-15754.

52. Russell DW, Brown MS, Goldstein JL. Different combinations of cysteine-rich repeats mediate binding of low density lipoprotein receptor to two different proteins. J Biol Chem 1989; 264:21682-21688.

53. Kim D, Magoori K, Inoue TR et al. Exon/intron organization, chromosome localization, alternative splicing, and transcription units of the human apolipoprotein E receptor 2 gene. J Biol Chem 1997; 272:8498-8504.

54. Brandes C, Novak S, Stockinger W et al. Avian and murine LR8B and human apolipoprotein E receptor 2: Differentially spliced products from corresponding genes. Genomics 1997; 42:185-191.

55. Fischer DG, Tal N, Novick D et al. An antiviral soluble form of the LDL receptor induced by interferon. Science 1993; 262:250-253.

56. Quinn KA, Grimsley PG, Dai Y-P et al. Soluble low density lipoprotein receptor-related protein (LRP) circulates in human plasma. J Biol Chem 1997; 272:23946-23951.

57. Rebeck GW, Harr S, West HL et al. Apolipoprotein E, LRP, and Alzheimer disease: New observations of shed receptors and isoform specific complex formation in CSF. Soc Neurosci (Abstract) 1994; 20:1076.

58. Bachinsky DR, Zheng G, Niles JL et al. Detection of two forms of gp330. Am J Path 1993; 143:598-611.

59. Freeman MW. Scavenger receptors in atherosclerosis. Current Opin Hematol 1997; 4:41-47.

60. Krieger M, Herz J. Structures and functions of multiligand lipoprotein receptors: Macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem 1994; 63:601-37.

61. Acton S, Rigotti A, Landschulz KT et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996; 271:518-520.

62. Christie RH, Freeman M, Hyman BT. Expression of the macrophage scavenger receptor, a multifunctional lipoprotein receptor, in microglia associated with senile plaques in Alzheimer's disease. Am J Path 1996; 148:399-403.

63. Huang Y, von Eckardstein A, Wu S et al. A plasma lipoprotein containing only apolipoprotein E and with y mobility on electrophoresis releases cholesterol from cells. Proc Natl Acad Sci USA 1994; 91:1834-1838.

64. Rebeck GW, Alonzo NC, Berezovska O et al. Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different apoE genotypes. Exp Neurol 1998; 149:175-182.

65. Bellosta S, Nathan BP, Orth M et al. Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J Biol Chem 1995; 270:27063-27071.

66. Fagan AM, Bu G, Sun Y et al. Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J Biol Chem 1996; 271:30121-30125.

67. Snipes GJ, McGuire CB, Norden JJ et al. Nerve injury stimulates the secretion of apolipoprotein E by non-neuronal cells. Proc Natl Acad Sci USA 1986; 83:1130-1134.

68. Ignatius MJ, Gebicke-Haerter PJ, Skene JHP et al. Expression of apolipoprotein E during nerve degeneration and regeneration. Proc Natl Acad Sci USA 1986; 83:1125-1129.

69. Boyles JK, Notterpek LM, Anderson LJ. Accumulation of apolipoproteins in the regenerating and remyelinating mammalian peripheral nerve. J Biol Chem 1990; 265:17805-17815.

70. Goodrum JF, Bouldin TW, Zhang SH et al. Nerve regeneration and cholesterol reutilization occur in the absence of apolipoproteins E and A-I in mice. J Neurochem 1995; 64:408-416.

71. Qian Z, Gilbert ME, Colicos MA et al. Tissue plasminogen activator is induced as an immediate-early gene during seizure and long term potentiation. Nature 1993; 361:453-457.

72. Mori T, Iijima N, Kitabatake K et al. a2-Macroglobulin is an astroglia-derived neurite-promoting factor for cultured neurons from rat central nervous system. Brain Res 1990; 527:55-61.

73. Kawamata T, Tooyama I, Yamada T et al. Lactotransferrin immunocytochemistry in Alzheimer and normal human brain. Am J Path 1993; 142:1574-1585.

74. de Silva HV, Harmony JAK, Stuart WD et al. Apolipoprotein J: Structure and tissue and distribution. Biochem 1990; 29:5380-5389.

75. Holtzman DM, Pitas RE, Kilbridge J et al. Low density lipoprotein receptor-related protein mediates apolipoprotein E-dependent neurite outgrowth in a central nervous system-derived neuronal cell line. Proc Natl Acad Sci USA 1995; 92:9480-9484.

76. Ishii M, Osada T, Gliemann J et al. Neurite-promoting effect of a2-macroglobulin in rat cerebral cortex is mainly associated with a2-macroglobulin receptor. Brain Res 1996; 737:269-274.

77. Schmechel DE, Saunders AM, Strittmatter WJ et al. Increased amyloid p-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer's disease. Proc Natl Acad Sci 1993; 90:9649-9653.

78. Gomez-Isla T, West HL, Rebeck GW et al. Clinical and pathological correlates of apolipoprotein E e4 in Alzheimer disease. Ann Neurol 1996; 39:62-70.

79. Strittmatter WJ, Weisgraber KH, Huang D et al. Binding of human apolipoprotein E to pA4 peptide: Isoform specific effects and implications for late onset Alzheimer disease. Proc Natl Acad Sci USA 1993; 90:8098-8102.

80. LaDu MJ, Pederson TM, Frail DE et al. Purification of apolipoprotein E attenuates isoform-specific binding to p-amyloid. J Biol Chem 1995; 270:9039-9042.

81. Ma J, Yee A, Brewer Jr AYH et al. Amyloid-associated proteins a1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer p-protein into filaments. Nature 1994; 372:92-94.

82. Sanan DA, Weisgraber KH, Russell SJ et al. Apolipoprotein E associates with p amyloid peptide of Alzheimer's disease to form novel monofibrils. J Clin Invest 1994; 94:860-869.

83. Wisniewski T, Castano EM, Golabek A et al. Acceleration of Alzheimer's disease fibril formation by apolipoprotein E in vitro. Am J Path 1994; 145:1030-1035.

84. Bales KR, Verina T, Dodel RC et al. Lack of apolipoprotein E dramatically reduces amyloid b-peptide deposition. Nature Genet 1997; 17:263-264.

85. Jordan J, Galindo MF, Miller RJ et al. Isoform-specific effect of apolipoprotein E on cell survival and p-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J Neurosci 1998; 18:195-204.

86. Urmoneit B, Prikulis I, Wihl G et al. Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: Implications for cerebral amyloid angiopathy. Lab Invest 1997; 77:157-166.

87. Zlokovic BV, Martel CL, Matsubara E et al. Glycoprotein 330/megalin: Probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid ß at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci USA 1996; 93:4229-4234.

88. Hammand SM, Ranganathan S, Loukinova E et al. Interaction of apolipoprotein J-amyloid ß peptide complex with low density lipoprotein receptor-related protein-2/megalin. J Biol Chem 1997; 272:18644-18649.

89. El Khoury J, Hickman SE, Thomas CA et al. Scavenger receptor-mediated adhesion of microglia to ß-amyloid fibrils. Nature 1996; 382:716-719.

90. Paresce DM, Ghosh RN, Maxfield FR. Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 1996; 17:553-565.

91. Kounnas MZ, Moir RD, Rebeck GW et al. LDL receptor-related protein, a multifunctional apoE receptor, binds secreted ß-amyloid precursor protein and mediates its degradation. Cell 1995; 82:331-340.

92. Knauer MF, Orlando RA, Glabe CG. Cell surface APP751 forms complexes with protease nexin 2 ligands and is internalized via the low density lipoprotein receptor-related protein (LRP). Brain Res 1996; 740:6-14.

93. Lendon CL, Talbot CJ, Craddock NJ et al. Genetic association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population. Neurosci Lett 1997; 222:187-190.

94. Chung H, Roberts CT, S G et al. Lack of association of trinucleotide repeat polymorphisms in the very-low-density lipoprotein receptor gene with Alzheimer's disease. Ann Neurol 1996; 39:800-803.

95. Pritchard ML, Saunders AM, Gaskell PC et al. No association between very low density lipoprotein receptor (VLDL-R) and Alzheimer disease in American Caucasians. Neurosci Lett 1996; 209:105-108.

96. Wavrant-DeVrieze F, Perez-Tur J, Lambert J-C et al. Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease. Neurosci Lett 1997; 227:68-70.

97. Clatworthy AE, Gomez-Isla T, Rebeck GW et al. Lack of association of a polymorphism in the low density lipoprotein receptor-related protein gene with Alzheimer disease. Arch Neurol 1997; 54:1289-1292.

98. Kang DE, Saitoh T, Chen X et al. Genetic association of the low-density lipoprotein receptor-related protein gene (LRP), an apolipoprotein E receptor, with late-onset Alzheimer's disease. Neurol 1997; 49:56-61.

99. Hollenbach E, Ackermann S, Hyman BT et al. Confirmation of an association between a polymorphism in exon 3 of the low density lipoprotein receptor-related protein gene and Alzheimer's disease. Neurol 1998; 50:1905-1907.

100. Kamboh MI, Ferrell RE, DeKosky ST. Genetic association studies between Alzheimer's disease and two polymorphisms in the low density lipoprotein receptor-related protein gene. Neurosci Lett 1998; 244:65-68.

101. Baum L, Chen L, Ng H-K et al. Low density lipoprotein receptor related protein gene exon 3 polymorphism association with Alzheimer disease in Chinese. Neurosci Lett 1998; 247:33-36.

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment