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PMID: 20005821 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.

Neuron ·Vol. 64 ·No. 5 ·2009-12-10 ·Pages 632-44

Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM

Abstract

Apolipoprotein E (APOE) is the strongest genetic risk factor for Alzheimer's disease (AD). Previous studies suggest that the effect of apoE on amyloid-beta (A beta) accumulation plays a major role in AD pathogenesis. Therefore, understanding proteins that control apoE metabolism may provide new targets for regulating A beta levels. LDLR, a member of the LDL receptor family, binds to apoE, yet its potential role in AD pathogenesis remains unclear. We hypothesized that LDLR overexpression in the brain would decrease apoE levels, enhance A beta clearance, and decrease A beta deposition. To test our hypothesis, we created several transgenic mice that overexpress LDLR in the brain and found that apoE levels in these mice decreased by 50%-90%. Furthermore, LDLR overexpression dramatically reduced A beta aggregation and enhanced A beta clearance from the brain extracellular space. Plaque-associated neuroinflammatory responses were attenuated in LDLR transgenic mice. These findings suggest that increasing LDLR levels may represent a novel AD treatment strategy.

MeSH Terms
Amyloid/metabolism Amyloid beta-Peptides/metabolism Amyloid beta-Protein Precursor/genetics Animals Animals, Newborn Apolipoproteins E/metabolism Astrocytes/metabolism Brain/cytology,metabolism CD11b Antigen/metabolism Cells, Cultured Embryo, Mammalian Extracellular Space/metabolism Female Gene Expression Regulation/genetics Humans Leukocyte Common Antigens/metabolism Mice Mice, Transgenic Neurons/metabolism Presenilin-1 Receptors, LDL/genetics,metabolism
Chemicals
Amyloid Amyloid beta-Peptides Amyloid beta-Protein Precursor Apolipoproteins E CD11b Antigen PSEN1 protein, human Presenilin-1 Receptors, LDL Leukocyte Common Antigens
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Kim Jungsu
Department of Neurology, Developmental Biology, Hope Center for Neurological Disorders, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Castellano Joseph M
Jiang Hong
Basak Jacob M
Parsadanian Maia
Pham Vi
Mason Stephanie M
Paul Steven M
Holtzman David M
References (63)
63 references, click to expand
  1. No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk.
    Am J Med Genet B Neuropsychiatr Genet. 2006 Jul 5;141B(5):541-3 PMID: 16741934
  2. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1.
    Neuron. 2007 Oct 4;56(1):66-78 PMID: 17920016
  3. Effect of inhibiting N-glycosylation on the stability and binding activity of the low density lipoprotein receptor.
    J Biol Chem. 1989 May 25;264(15):8815-20 PMID: 2722801
  4. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition.
    Nat Genet. 1997 Nov;17(3):263-4 PMID: 9354781
  5. Gender differences in the amount and deposition of amyloidbeta in APPswe and PS1 double transgenic mice.
    Neurobiol Dis. 2003 Dec;14(3):318-27 PMID: 14678749
  6. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life.
    J Neurosci. 2003 Oct 1;23(26):8844-53 PMID: 14523085
  7. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.
    Nat Genet. 2007 Jan;39(1):17-23 PMID: 17192785
  8. A vector for expressing foreign genes in the brains and hearts of transgenic mice.
    Genet Anal. 1996 Dec;13(6):159-63 PMID: 9117892
  9. The role of apolipoprotein E in Alzheimer's disease.
    Neuron. 2009 Aug 13;63(3):287-303 PMID: 19679070
  10. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system.
    J Cereb Blood Flow Metab. 2007 May;27(5):909-18 PMID: 17077814
  11. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease.
    J Biol Chem. 2005 Dec 30;280(52):43243-56 PMID: 16207707
  12. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model.
    Ann Neurol. 2000 Jun;47(6):739-47 PMID: 10852539
  13. Extracellular amyloid formation and associated pathology in neural grafts.
    Nat Neurosci. 2003 Apr;6(4):370-7 PMID: 12598899
  14. Potential genetic markers of sporadic Alzheimer's dementia.
    Psychiatr Genet. 2001 Sep;11(3):115-22 PMID: 11702052
  15. Heterogeneity of apolipoprotein E epitope expression on human lipoproteins: importance for apolipoprotein E function.
    J Lipid Res. 1988 Oct;29(10):1309-25 PMID: 2466929
  16. Inflammation in Alzheimer disease: driving force, bystander or beneficial response?
    Nat Med. 2006 Sep;12(9):1005-15 PMID: 16960575
  17. In vivo calibration of microdialysis probes for exogenous compounds.
    Anal Chem. 1992 Mar 15;64(6):577-83 PMID: 1580357
  18. Modulation of beta-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family.
    Mol Neurodegener. 2006 Aug 18;1:8 PMID: 16930455
  19. Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor.
    J Neurochem. 2007 Aug;102(4):1220-31 PMID: 17472705
  20. The Alzheimer's disease beta-secretase enzyme, BACE1.
    Mol Neurodegener. 2007 Nov 15;2:22 PMID: 18005427
  21. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.
    Nature. 2008 Feb 7;451(7179):720-4 PMID: 18256671
  22. Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice.
    Am J Pathol. 2001 Mar;158(3):1173-7 PMID: 11238065
  23. A hundred years of Alzheimer's disease research.
    Neuron. 2006 Oct 5;52(1):3-13 PMID: 17015223
  24. Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease.
    Hum Mol Genet. 2008 Apr 1;17(7):929-35 PMID: 18065781
  25. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15233-8 PMID: 10611368
  26. Apolipoprotein E receptors in the nervous system.
    Curr Opin Lipidol. 2009 Jun;20(3):190-6 PMID: 19433918
  27. The cytoplasmic domain of the LDL receptor-related protein regulates multiple steps in APP processing.
    EMBO J. 2002 Nov 1;21(21):5691-700 PMID: 12411487
  28. The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice.
    J Biol Chem. 2005 Jul 8;280(27):25754-9 PMID: 15888448
  29. Disease modifying therapy for AD?
    J Neurochem. 2006 Nov;99(3):689-707 PMID: 17076654
  30. Genetic association of low density lipoprotein receptor and Alzheimer's disease.
    Neurobiol Aging. 2005 Jan;26(1):1-7 PMID: 15585340
  31. Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein.
    Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):1075-80 PMID: 14732699
  32. Modulation of beta-amyloid precursor protein processing by the low density lipoprotein receptor-related protein (LRP). Evidence that LRP contributes to the pathogenesis of Alzheimer's disease.
    J Biol Chem. 2000 Mar 10;275(10):7410-5 PMID: 10702315
  33. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10843-8 PMID: 12145324
  34. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.
    J Lipid Res. 1999 Jan;40(1):1-16 PMID: 9869645
  35. Abeta40 inhibits amyloid deposition in vivo.
    J Neurosci. 2007 Jan 17;27(3):627-33 PMID: 17234594
  36. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group.
    Neurology. 1999 Dec 10;53(9):1992-7 PMID: 10599770
  37. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo.
    Neuron. 2004 Jan 22;41(2):193-202 PMID: 14741101
  38. Lipoprotein receptors in the nervous system.
    Annu Rev Biochem. 2002;71:405-34 PMID: 12045102
  39. gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?
    Nat Rev Neurosci. 2002 Apr;3(4):281-90 PMID: 11967558
  40. Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer's disease, but does extend lifespan.
    Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3502-6 PMID: 19204288
  41. Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease.
    J Biol Chem. 2005 Dec 30;280(52):43236-42 PMID: 16207708
  42. Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors.
    Science. 1990 Nov 30;250(4985):1273-5 PMID: 2244210
  43. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain.
    J Clin Invest. 2008 Dec;118(12):4002-13 PMID: 19033669
  44. Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis.
    J Neurosci. 2008 Nov 12;28(46):12097-106 PMID: 19005074
  45. Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease.
    J Clin Invest. 2008 Feb;118(2):671-82 PMID: 18202749
  46. Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice.
    Clin Chem Lab Med. 2005;43(5):470-9 PMID: 15899668
  47. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice.
    J Biol Chem. 2005 Dec 30;280(52):43224-35 PMID: 16207713
  48. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.
    Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7 PMID: 10694577
  49. ApoE promotes the proteolytic degradation of Abeta.
    Neuron. 2008 Jun 12;58(5):681-93 PMID: 18549781
  50. Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice.
    Neurobiol Aging. 2006 Nov;27(11):1632-43 PMID: 16236385
  51. Intramembrane proteolysis by presenilins.
    Nat Rev Mol Cell Biol. 2000 Dec;1(3):217-24 PMID: 11252897
  52. Functional interaction between APOE4 and LDL receptor isoforms in Alzheimer's disease.
    J Med Genet. 2005 Feb;42(2):129-31 PMID: 15689450
  53. Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer's disease animal model.
    Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19198-203 PMID: 16365303
  54. The LDLR locus in Alzheimer's disease: a family-based study and meta-analysis of case-control data.
    Neurobiol Aging. 2007 Jan;28(1):18.e1-4 PMID: 16378661
  55. Genetic study evaluating LDLR polymorphisms and Alzheimer's disease.
    Neurobiol Aging. 2008 Jun;29(6):848-55 PMID: 17239995
  56. Brainstem concentrations of cholesterol are not influenced by genetic ablation of the low-density lipoprotein receptor.
    Neurochem Res. 2009 Feb;34(2):311-5 PMID: 18607722
  57. Mechanisms of disease: genetic causes of familial hypercholesterolemia.
    Nat Clin Pract Cardiovasc Med. 2007 Apr;4(4):214-25 PMID: 17380167
  58. A receptor-mediated pathway for cholesterol homeostasis.
    Science. 1986 Apr 4;232(4746):34-47 PMID: 3513311
  59. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice.
    J Neurosci. 2007 Nov 28;27(48):13357-65 PMID: 18045930
  60. Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice.
    Science. 1988 Mar 11;239(4845):1277-81 PMID: 3344433
  61. Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse.
    Brain Res Dev Brain Res. 2003 Dec 19;146(1-2):87-98 PMID: 14643015
  62. Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice.
    J Biol Chem. 2006 Nov 24;281(47):36180-6 PMID: 17012232
  63. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase.
    Hum Mol Genet. 2004 Jan 15;13(2):159-70 PMID: 14645205
Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2009.11.013
Published
2009-12-10
Pages
632-44
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2787195
Subset
IM
Grants
NINDS NIH HHS · P30 NS057105-04 · United States
NIA NIH HHS · K01 AG029524-03 · United States
NIDDK NIH HHS · P30 DK056341 · United States
NINDS NIH HHS · P01 NS032636 · United States
NIA NIH HHS · AG13956 · United States
NIA NIH HHS · R37 AG013956 · United States
NIA NIH HHS · F31 AG034004 · United States
NINDS NIH HHS · P01 NS032636-140007 · United States
NIDDK NIH HHS · P30 DK056341-09 · United States
NINDS NIH HHS · P30 NS057105 · United States
NIA NIH HHS · K01 AG029524 · United States
NIA NIH HHS · R37 AG013956-15 · United States
NIA NIH HHS · R01 AG013956 · United States
NIA NIH HHS · R37 AG013956-14 · United States
NIA NIH HHS · AG034004-01A1 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2009.11.013 PMC Full Text View journal details
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