Skip to main content

Advertisement

SpringerLink
Log in

Is the LDL Receptor Involved in Cortical Amyloid Protein Clearance?

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

This article puts forward the hypothesis that the Low Density Lipid Receptor (LDLR) is one of the molecules that is involved in the clearance of amyloid proteins in the brain and that it may play a role in Alzheimer’s Disease (AD) via its up-regulation by statins. The hypothesis is built on the following observations: a-statins (which have been shown to increase LDLR in astrocytes, see below) have a beneficial role in AD, b-defects in the LDL receptor gene are found in AD, c-molecules with similar structure to the LDLR have been shown to clear amyloid protein from the brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, Multhaup G, Beyreuther K, Muller-Hill B (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325:733–736

    Article  PubMed  CAS  Google Scholar 

  2. Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (1990) Genomic organization of the human amyloid beta-protein precursor gene. Gene 87:257–263

    Article  PubMed  CAS  Google Scholar 

  3. Kitaguchi N, Takahashi Y, Tokushima Y, Shiojiri S, Ito H (1988) Novel precursor of Alzheimer’s disease amyloid protein shows protease inhibitory activity. Nature 331, 530–532;doi:10.1038/331530a0

    Article  PubMed  CAS  Google Scholar 

  4. Tanzi RE, McClatchey AI, Lamperti ED, Villa-Komaroff L, Gusella JF, Neve RL (1988) Protease inhibitor domain encoded by an amyloid protein precursor mRNA associated with Alzheimer’s disease. Nature 331:528–532

    Article  PubMed  CAS  Google Scholar 

  5. de Sauvage F, Octave JN (1989) A novel mRNA of the A4 amyloid precursor gene coding for a possibly secreted protein. Science Aug 11, 245(4918):651–653

    Google Scholar 

  6. Oltersdorf T, Ward PJ, Henriksson T, Beattie EC, Neve R, Lieberburg I, Fritz LC (1990) The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/degradative pathway. J Biol Chem 265: 4492–4497

    PubMed  CAS  Google Scholar 

  7. Sinha S, Dovey HF, Seubert P, Ward PJ, Balcher RW, Blaber M, Bradshaw RA, Arici M, Mobley WC, Lieberburg I (1990) The protease inhibitory properties of the Alzheimer’s beta-amyloid precursor protein. J Biol Chem 265: 8983–8985

    PubMed  CAS  Google Scholar 

  8. Konig G, Monning U, Czech C, Prior R, Banati R, Schreiter-Gasser U, Bauer J, Masters CL, Beyreuther K (1992) Identification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells. J Biol Chem 267(15):10804–10809.

    PubMed  CAS  Google Scholar 

  9. Estus S, Golde TE, Kunishita T, Blades D, Lowery D, Eisen M, Usiak M, Qu XM, Tabira T, Greenberg BD, (1992a) Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor. Science 255(5045):726–728

    Article  CAS  Google Scholar 

  10. Estus S, Golde TE, Younkin SG (1992b) Normal processing of the Alzheimer’s disease amyloid beta protein precursor generates potentially amyloidogenic carboxyl-terminal derivatives. Ann N Y Acad Sci Dec 31 674:138–148

    Article  CAS  Google Scholar 

  11. Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science 255(5045):728–730

    Article  PubMed  CAS  Google Scholar 

  12. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, Sinha S, Schiossmacher M, Whaley J, Swindlehurst C, McCormack R, Wolfert R, Selkoe D, Lieberburg L & Schenk D (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359, 325–327; doi:10.1038/359325a0

    Google Scholar 

  13. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890

    Article  PubMed  CAS  Google Scholar 

  14. Checler F (1995) Processing of the beta-amyloid precursor protein and its regulation in Alzheimer’s disease. J Neurochem 65: 1431–1444

    Article  PubMed  CAS  Google Scholar 

  15. Mudher A, Lovestone S (2002) Alzheimer’s disease – do tauists and baptists finally shake hands? Trends Neurosci 25(1):22–26

    Article  PubMed  CAS  Google Scholar 

  16. Selkoe DJ (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol 53(5):438–447

    Article  PubMed  CAS  Google Scholar 

  17. Uwe B, Stolt P, Herz J (2004) Functions of lipoprotein receptors in neurons. J Lipid Res 45:403–409

    Google Scholar 

  18. Tolleshaug H, Goldstein JL, Schneider WJ, Brown MS (1982) Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia. Cell 30(3):715–724

    Article  PubMed  CAS  Google Scholar 

  19. Brown MS, Goldstein JL (1979) Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci USA 76(7):3330–3337

    Article  PubMed  CAS  Google Scholar 

  20. Endo A, Kuroda M (1976) Citrinin, an inhibitor of cholesterol synthesis. J Antibiot (Tokyo) 29(8):841–843

    CAS  Google Scholar 

  21. Pavlov OV, Bobryshev YuV, Balabanov YuV, Ashwell K (1995) An in vitro study of the effects of lovastatin on human fetal brain cells. Neurotoxicol Teratol 17(1):31–39

    Article  PubMed  CAS  Google Scholar 

  22. Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G (2000) Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol 57: 1439–1443

    Article  PubMed  CAS  Google Scholar 

  23. Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA (2000) Statins and the risk of dementia. Lancet 356: 1627–1631

    Article  PubMed  CAS  Google Scholar 

  24. Hajjar I, Schumpert J, Hirth V,Wieland D, Eleazer GP (2002) The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment. J Gerontol A Biol Sci Med Sci 57: M414–M418

    PubMed  Google Scholar 

  25. Rockwood K, Kirkland S, Hogan DB, MacKnight C, Merry H, Verreault R, Wolfson C, McDowell I (2002) Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 59: 223–227

    Article  PubMed  Google Scholar 

  26. Zamrini E, McGwin G, Roseman JM (2004) Association between statin use and Alzheimer’s disease. Neuroepidemiology 23: 94–98

    Article  PubMed  Google Scholar 

  27. Masse I, Bordet R, Deplanque D, Al Khedr A, Richard F, Libersa C, Pasquier F (2005) Lipid lowering agents are associated with a slower cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76(12):1624–1629

    Article  PubMed  CAS  Google Scholar 

  28. Simons M, Schwarzler F, Lutjohann D, von Bergmann K, Beyreuther K, Dichgans J, Wormstall H, Hartmann T, Schulz JB (2002) Treatment with simvastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomised, placebo-controlled, double-blind trial. Ann Neurol 52: 346–350

    Article  PubMed  CAS  Google Scholar 

  29. Hoglund K, Wiklund O, Vanderstichele H, Eikenberg O, Vanmechelen E, Blennow K (2004) Plasma levels of beta-amyloid (1–40), beta-amyloid (1–42), and total beta-amyloid remain unaffected in adult patients with hypercholesterolaemia after treatment with statins. Arch Neurol 61: 333–337

    Article  PubMed  Google Scholar 

  30. Breitner JCS, Zandi PP, Li G, Rea TG, Psaty BM (2004) Can statins prevent AD, or are they just prescribed less often to those with cognitive disorders?. Neurobiol Aging 25[S2]: 5

    Article  Google Scholar 

  31. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360(9346):1623–1630

    Article  PubMed  CAS  Google Scholar 

  32. Wolozin B, Brown J 3rd, Theisler C, Silberman S (2004) The cellular biochemistry of cholesterol and statins: insights into the pathophysiology and therapy of Alzheimer’s disease. CNS Drug Rev 10(2):127–146

    Article  PubMed  CAS  Google Scholar 

  33. Zandi PP, Sparks DL, Khachaturian AS, Tschanz J, Norton M, Steinberg M, Welsh-Bohmer KA, Breitner JC Cache County Study investigators (2005). Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study Arch Gen Psychiatry 62(2):217–224

    Article  CAS  Google Scholar 

  34. Park IH, Hwang EM, Hong HS, Boo JH, Oh SS, Lee J, Jung MW, Bang OY, Kim SU, Mook-Jung I (2003) Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice. Neurobiol Aging 24:637–643

    Article  PubMed  CAS  Google Scholar 

  35. Retz W, Thome J, Durany N, Harsanyi A, Retz-Junginger P, Kornhuber J, Riederer P, Rosler M (2001) Potential genetic markers of sporadic Alzheimer’s dementia. Psychiatr Genet 11(3):115–122

    Article  PubMed  CAS  Google Scholar 

  36. Luedecking-Zimmer E, DeKosky ST, Chen Q, Barmada MM, Kamboh MI (2002) Investigation of oxidized LDL-receptor 1 (OLR1) as the candidate gene for Alzheimer’s disease on chromosome 12. Hum Genet 111(4–5):443–451

    Article  PubMed  CAS  Google Scholar 

  37. D’IntronoA, Solfrizzi V, Colacicco AM, Capurso C, Torres F, Capurso SA, Capurso A, Panza F (2005) Polymorphisms in the oxidized low-density lipoprotein receptor-1 gene and risk of Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 60(3):280–284

    Google Scholar 

  38. Gopalraj RK, Zhu H, Kelly JF, Mendiondo M, Pulliam JF, Bennett DA, Estus S (2005) Genetic association of low density lipoprotein receptor and Alzheimer’s disease. Neurobiol Aging 26(1):1–7

    Article  PubMed  CAS  Google Scholar 

  39. Bertram L, Parkinson M, Mullin K, Menon R, Blacker D, Tanzi RE (2004) No association between a previously reported OLR1 3’ UTR polymorphism and Alzheimer’s disease in a large family sample. J Med Genet 41(4):286–288

    Article  PubMed  CAS  Google Scholar 

  40. Papassotiropoulos A, Wollmer MA, Tsolaki M, Brunner F, Molyva D, Lutjohann D, Nitsch RM, Hock C (2005) A cluster of cholesterol-related genes confers susceptibility for Alzheimer’s disease. J Clin Psychiatry 66(7):940–947

    Article  PubMed  CAS  Google Scholar 

  41. Shi J, Tian J, Pritchard A, Lendon C, Lambert JC, Iwatsubo T, Mann DM (2006) A 3′-UTR polymorphism in the oxidized LDL receptor 1 gene increases Abeta(40) load as cerebral amyloid angiopathy in Alzheimer’s disease. Acta Neuropathol (Berl) 111(1):15–20

    Article  CAS  Google Scholar 

  42. Cao D, Fukuchi KI, Wan H, Kim H, Li L (2005) Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice. Neurobiol Aging

  43. Yang DS, Small DH, Seydel U, Smith JD, Hallmayer J, Gandy SE, Martins RN (1999) Apolipoprotein E promotes the binding and uptake of beta-amyloid into Chinese hamster ovary cells in an isoform-specific manner. Neuroscience 90(4):1217–1226

    Article  PubMed  CAS  Google Scholar 

  44. Qiu Z, Strickland DK, Hyman BT, Rebeck GW (1999) Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons. J Neurochem 73(4):1393–1398

    Article  PubMed  CAS  Google Scholar 

  45. Kang DE, Pietrzik CU, Baum L, Chevallier N, Merriam DE, Kounnas MZ, Wagner SL, Troncoso JC, Kawas CH, Katzman R, Koo EH (2000) Modulation of amyloid beta-protein clearance and Alzheimer’s disease susceptibility by the LDL receptor-related protein pathway. J Clin Invest 106(9):1159–1166

    Article  PubMed  CAS  Google Scholar 

  46. Deane R, Wu Z, Zlokovic B (2004a) Beta-peptide clearance through transport across the blood–brain barrier RAGE (Yin) versus LRP (Yang) balance regulates. Alzheimer Amyloid Stroke 35:2628–2631

    CAS  Google Scholar 

  47. Deane R, Wu Z, Sagare A, Davis J, Du Yan S, Hamm K, Xu F, Parisi M, LaRue B, Hu HW, Spijkers P, Guo H, Song X, Lenting PJ, Van Nostrand WE, Zlokovic BV (2004b) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron Aug 5, 43(3):333–344

  48. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. J Clin Invest 106:1489–1499

    Article  PubMed  CAS  Google Scholar 

  49. Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 11(4):575–580

    Article  PubMed  CAS  Google Scholar 

  50. Kounnas MZ, Moir RD, Rebeck GW, Bush AI, Argraves WS, Tanzi RE, Hyman BT, Strickland DK (1995) LDL receptor related protein, a multifunctional ApoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell 82(2):331–340

    Article  PubMed  CAS  Google Scholar 

  51. Van Uden E, Mallory M, Veinbergs I, Alford M, Rockenstein E, Masliah E (2002) Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein. J Neurosci 122(21):9298–9304

    Google Scholar 

  52. Zerbinatti and Bu (2005) LRP and Alzheimer’s disease Rev Neurosci. 16(2):123–135. Review

  53. Harris-White, Frautschy (2005) Low density lipoprotein receptor-related proteins (LRPs), Alzheimer’s and cognition Curr Drug Targets. CNS Neurol Disord 4(5):469–480

    Article  CAS  Google Scholar 

  54. Kim S, Kim CH, Vaziri ND (2005) Upregulation of hepatic LDL receptor-related protein in nephrotic syndrome: response to statin therapy. Am J Physiol Endocrinol Metab 288(4):E813–817

    Article  PubMed  CAS  Google Scholar 

  55. Suzuki H, Yamazaki H, Aoki T, Kojima J, Tamaki T, Sato F, Kitahara M, Saito Y (2000) Lipid-lowering and antiatherosclerotic effect of NK-104, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits. Arzneimittelforschung 50(11):995–1003

    PubMed  CAS  Google Scholar 

  56. Zlokovic B (2005) Neurovascular Mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 28(4):202–208

    Google Scholar 

  57. Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, Brooks AI, Kanagala S, Rubio A, Sagare A, Liu D, Li F, Armstrong D, Gasiewicz T, Zidovetzki R, Song X, Hofman F, Zlokovic BV (2005) Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med 11(9):959–965

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. St. John’s Hospital, Orthogeriatrics, Livingston, EH54 6PS, UK

    Yasir Abdulkarim

  2. St. Mary’s Hospital, Geriatrics, Dublin, Ireland

    Zeyad Hameed

Authors
  1. Yasir Abdulkarim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeyad Hameed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasir Abdulkarim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abdulkarim, Y., Hameed, Z. Is the LDL Receptor Involved in Cortical Amyloid Protein Clearance?. Neurochem Res 31, 839–847 (2006). https://doi.org/10.1007/s11064-006-9084-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-006-9084-0

Keywords

Search

Navigation