Cellular and Molecular Neurobiology

, Volume 32, Issue 3, pp 409–421 | Cite as

SorLA in Glia: Shared Subcellular Distribution Patterns with Caveolin-1

  • Iris K. Salgado
  • Melissa Serrano
  • José O. García
  • Namyr A. Martínez
  • Héctor M. Maldonado
  • Carlos A. Báez-Pagán
  • José A. Lasalde-Dominicci
  • Walter I. SilvaEmail author
Original Research


SorLA is an established sorting and trafficking protein in neurons with demonstrated relevance to Alzheimer’s disease (AD). It shares these roles with the caveolins, markers of membrane rafts microdomains. To further our knowledge on sorLA’s expression and traffic, we studied sorLA expression in various cultured glia and its relation to caveolin-1 (cav-1), a caveolar microdomain marker. RT-PCR and immunoblots demonstrated sorLA expression in rat C6 glioma, primary cultures of rat astrocytes (PCRA), and human astrocytoma 1321N1 cells. PCRA were determined to express the highest levels of sorLA’s message. Induction of differentiation of C6 cells into an astrocyte-like phenotype led to a significant decrease in sorLA’s mRNA and protein expression. A set of complementary experimental approaches establish that sorLA and cav-1 directly or indirectly interact in glia: (1) co-fractionation in light-density membrane raft fractions of rat C6 glioma, PCRA, and human 1321N1 astrocytoma cells; (2) a subcellular co-localization distribution pattern in vesicular perinuclear compartments seen via confocal imaging in C6 and PCRA; (3) additional confocal analysis in C6 cells suggesting that the perinuclear compartments correspond to their co-localization in early endosomes and the trans-Golgi; and; (4) co-immunoprecipitation data strongly supporting their direct or indirect physical interaction. These findings further establish that sorLA is expressed in glia and that it shares its subcellular distribution pattern with cav-1. A direct or indirect cav-1/sorLA interaction could modify the trafficking and sorting functions of sorLA in glia and its proposed neuroprotective role in AD.


Alzheimer’s disease Caveolae Glia Early endosome Trans-Golgi network 



This study was supported in part by the NIH-MBRS-SCORE grant S06-GM08224 awarded to WIS, and RCMI Program G12RR03051 at UPR-MSC. Graduate students IKS, JOG, and NAM were supported by the NIGMS-MBRS-RISE grant GM61838 at UPR-MSC. The authors are also grateful to Mr. Bismarck Madera for his valuable assistance with the LSCM studies.


  1. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci 102:13461–13466PubMedCrossRefGoogle Scholar
  2. Beffert U, Stolt PC, Herz J (2004) Functions of lipoprotein receptors in neurons. J Lipid Res 45:403–409PubMedCrossRefGoogle Scholar
  3. Bettens K, Brouwers N, Engelborghs S, De Deyn PP, Van Broeckhoven C, Sleegers K (2008) SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat 29:769–770PubMedCrossRefGoogle Scholar
  4. Bujo H, Saito Y (2000) Markedly induced expression of LR11 in atherosclerosis. J Atheroscler Thromb 7:21–25PubMedGoogle Scholar
  5. Cam JA, Bu G (2006) Modulation of beta-amyloid precursor protein trafficking and processing by the low-density lipoprotein receptor family. Mol Neurodegener 1:8PubMedCrossRefGoogle Scholar
  6. Chorna NE, Santiago-Pérez LI, Erb L, Seye C, Neary JT, Sun GY, Weisman GA, González FA (2004) P2Y2 receptors activate neuroprotective mechanisms in astrocytic cells. J Neurochem 91:119–132PubMedCrossRefGoogle Scholar
  7. Costes SV, Daelemans D, Cho EH, Dobbin Z, Pavlakis G, Lockett S (2004) Automatic and quantitative measurement of protein-protein colocalization in live cells. Biophys J 86:3993–4003PubMedCrossRefGoogle Scholar
  8. Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes: implications for their role in neurological disease. Neuroscience 54(1):15–36PubMedCrossRefGoogle Scholar
  9. Fellin T, Carmignoto G (2004) Neuron-to astrocyte signaling in the brain represents a distinct multifunctional unit. J Physiol 559:3–15PubMedCrossRefGoogle Scholar
  10. Gaudreault S, Dea D, Poirier J (2004) Increased caveolin-1 expression in Alzheimer’s disease brain. Neurobiol Aging 25(6):753–759PubMedCrossRefGoogle Scholar
  11. Gaul G, Dutly F, Frei K, Foguet M, Lübbert H (1992) APP RNA splicing is not affected by differentiation of neurons and glia in culture. FEBS Lett 307:329–332PubMedCrossRefGoogle Scholar
  12. Hansson E, Rönnbäck L (2003) Glial neuronal signaling in the central nervous system. FASEB J 17:341–348PubMedCrossRefGoogle Scholar
  13. He X, Li F, Chang WP, Tang J (2005) GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem 280:11696–11703PubMedCrossRefGoogle Scholar
  14. Herz J, Chen Y, Masiulis I, Zhou L (2009) Expanding functions of lipoprotein receptors. J Lipid Res 50:S287–S292PubMedCrossRefGoogle Scholar
  15. Huse J, Doms RW (2001) Neurotoxic traffic: uncovering the mechanics of amyloid production in Alzheimer’s disease. Traffic 2:75–81PubMedCrossRefGoogle Scholar
  16. Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T (1998) Caveolae, plasma membrane microdomains for α-secretase-mediated processing of the amyloid precursor protein. J Biol Chem 273:10485–10495PubMedCrossRefGoogle Scholar
  17. Jacobsen L, Madsen P, Nielsen MS, Geraerts WP, Glieman J, Smit AB, Petersen CM (2002) The sorLA cytoplasmic domain interacts with the GGA-1 and -2 and defines minimun requirements for GGA binding. FEBS Lett 511(1–3):155–158PubMedCrossRefGoogle Scholar
  18. Kanaki T, Bujo H, Hirayama S, Ishii I, Morisaki N, Schneider WJ, Saito Y (1999) Expression of LR11, a mosaic LDL receptor family member, is markedly increased in atherosclerotic lesions. Arterioscler Thromb Vasc Biol 19:2687–2695PubMedCrossRefGoogle Scholar
  19. Kang MJ, Chung YH, Hwang CI, Murata M, Fujimoto T, Mook-Jung IH, Cha CI, Park WY (2006) Caveolin-1 upregulation in senescent neurons alters amyloid precursor protein processing. Exp Mol Med 38:126–133PubMedGoogle Scholar
  20. Kato S, Gondo T, Hoshii Y, Takahashi M, Yamada M, Ishihara T (1998) Confocal observation of senile plaques in Alzheimer’s disease: senile plaque morphology and relationship between senile plaques and astrocytes. Pathol Int 48(5):332–340PubMedCrossRefGoogle Scholar
  21. Kölsch H, Jessen F, Wiltfang J, Lewczuk P, Dichgans M, Teipel SJ, Kornhuber J, Frölich L, Heuser I, Peters O, Wiese B, Kaduszkiewicz H, van den Bussche H, Hüll M, Kurz A, Rüther E, Henn FA, Maier W (2009) Association of SORL1 gene variants with Alzheimer’s disease. Brain Res 1264:1–6PubMedCrossRefGoogle Scholar
  22. Lackland J., Dreyfus CF (2002) Trophins as mediators of astrocytes effects in the aging and regenerating brain. In De Vellis JS (ed) Neuroglia in the aging brain, 1st edn. Human Press, Totowa, pp 199–216Google Scholar
  23. Lee JL, Cheng R, Schupf N, Manly J, Lantigua R, Stern Y, Rogaeva E, Wakutani Y, Farrer L, George-Hyslop PS, Mayeux R (2007) The association between genetic variants in sorL1 and Alzheimer’s disease in an urban, multiethnic, community-based cohort. Arch Neurol 64:501–506PubMedCrossRefGoogle Scholar
  24. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta c(t)) method. Methods 25:402–408PubMedCrossRefGoogle Scholar
  25. Macdonald TJ, Pollack IF, Okada H, Bhattacharya S, Lyons-Weileret J (2007) Progression-associated genes in astrocytoma identified by novel microarray gene expression data reanalysis. Meth Mol Biol 377:203–221CrossRefGoogle Scholar
  26. Manders EM, Stap J, Brakenhoff GJ, van Driel R, Aten JA (1992) Dynamics of three-dimensional replication patterns during the S-phase, analyzed by double labeling of DNA and confocal microscopy. J Cell Sci 103:857–862PubMedGoogle Scholar
  27. Marcusson E, Horazdovsky B, Cereghino J, Gharakhanian E, Emr S (1994) The sorting receptor yeast vacuolar carboxypeptidase Y is encoded by the VSP10 gene. Cell 77(4):579–586PubMedCrossRefGoogle Scholar
  28. Mattson MP, Chan SL (2003) Neuronal and glial calcium signaling in Alzheimer’s disease. Cell Calcium 34:385–397PubMedCrossRefGoogle Scholar
  29. Melgren RL (2008) Detergent-resistant membrane subfractions containing proteins of plasma membrane, mitochondrial, and internal membrane origins. J Biochem Biophys Methods 70:1029–1036CrossRefGoogle Scholar
  30. Morato E, Mayor F (1993) Production of the Alzheimer’s ß-amyloid peptide by C6 glioma cells. FEBS Lett 336:275–278PubMedCrossRefGoogle Scholar
  31. Motoi Y, Aizawa T, Haga S, Nakamura S, Namba Y, Ikeda K (1999) Neuronal localization of a novel mosaic apolipoprotein E receptor, LR11, in rat and human brain. Brain Res 833:209–215PubMedCrossRefGoogle Scholar
  32. Mrak RE, Griffin WS (2005) Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 26:349–354PubMedCrossRefGoogle Scholar
  33. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25(5):663–674PubMedCrossRefGoogle Scholar
  34. Nichols B (2003) Caveosomes and endocytosis of lipid rafts. J Cell Sci 116:4707–4714PubMedCrossRefGoogle Scholar
  35. Nielsen MS, Gustafsen C, Madsen P, Nyengaard JR, Hermey G, Bakke O, Mari M, Schu P, Pohlmann R, Dennes A, Petersen CM (2007) Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA. Mol Cell Biol 27:6842–6851PubMedCrossRefGoogle Scholar
  36. Nishiyama K, Trapp BD, Ikezu T, Ransohoff RM, Tomita T, Iwatsubo T, Kanazawa I, Hsiao KK, Lisanti MP, Okamoto T (1999) Caveolin-3 upregulation activates beta-secretase-mediated cleavage of the amyloid precursor protein in Alzheimer’s disease. J Neurosci 19:6538–6548PubMedGoogle Scholar
  37. Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603PubMedCrossRefGoogle Scholar
  38. Parton RK (2004) Caveolae meet endosomes: a stable relationship? Dev Cell 7:458–460PubMedCrossRefGoogle Scholar
  39. Pelkmans L, Kartenbeck J, Helenius A (2001) Caveolar endocytosis of simian virus 40 reveals a new two-step vesicular-transport pathway to the ER. Nat Cell Biol 3:473–483PubMedCrossRefGoogle Scholar
  40. Pelkmans L, Burli T, Zerial M, Helenius A (2004) Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic. Cell 118:767–780PubMedCrossRefGoogle Scholar
  41. Peters PJ, Mironov A Jr, Peretz D, van Donselaar E, Leclerc E, Erpel S, DeArmond SJ, Burton DR, Williamson RA, Vey M et al (2003) Trafficking of prion proteins through a caveolae-mediated endosomal pathway. J Cell Biol 162:703–717PubMedCrossRefGoogle Scholar
  42. Pike LJ (2006) Rafts defined: a report on the keystone symposium on lipid rafts and cell function. J Lipid Res 47:1597–1598PubMedCrossRefGoogle Scholar
  43. Poirier J (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer’s disease. Trends Neurosci 17:525–530PubMedCrossRefGoogle Scholar
  44. Poirier J (2005) Apolipoprotein E, cholesterol transport and synthesis in sporadic Alzheimer’s disease. Neurobiol Aging 26:355–361PubMedCrossRefGoogle Scholar
  45. Pol A, Calvo M, Lu A, Enrich C (1999) The “early-sorting” endocytic compartment of rat hepatocytes is involved in the intracellular pathway of caveolin-1 (VIP-21). Hepatol 29(6):1848–1857CrossRefGoogle Scholar
  46. Rajendran L, Simons K (2009) Membrane trafficking and targeting in Alzheimer’s disease. In St George-Hyslop P et al (eds) Intracellular traffic and neurodegenerative disorders, research and perspectives in Alzheimer’s Disease, Springer, Heidelberg, pp 103–113Google Scholar
  47. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K (2006) Alzheimer’s disease β-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci 103:11172–11177PubMedCrossRefGoogle Scholar
  48. Rajendran L, Knobloch M, Geiger KD, Dienel S, Nitsch R, Simons K, Konietzko U (2007) Increased abeta production leads to intracellular accumulation of abeta in flotillin-1-positive endosomes. Neurodegener Dis 4:164–170PubMedCrossRefGoogle Scholar
  49. Reid PC, Urano Y, Kodama T, Hamakubo T (2007) Alzheimer’s disease: cholesterol, membrane rafts, isoprenoids and statins. J Cell Mol Med 11:383–392PubMedCrossRefGoogle Scholar
  50. Ridet JL, Malhotra SK, Prvat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577PubMedCrossRefGoogle Scholar
  51. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H et al (2007) The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 39:168–177PubMedCrossRefGoogle Scholar
  52. Rogaeva E, Meng Y, Lee JH, Mayeux R, Farrer LA, St George-Hyslop P (2009) The sortilin-related receptor SORL1 is functionally and genetically associated with Alzheimer’s Disease. In St George-Hyslop P et al (eds) Intracellular traffic and neurodegenerative disorders, research and perspectives in Alzheimer’s Disease. Springer, BerlinGoogle Scholar
  53. Rohe M, Synowitz M, Glass R, Paul SM, Paul SM, Nykjaer A, Willnow TE (2009) Brain-derived neurotrophic factor reduces amyloidogenc processing through control of sorLA gene expression. J Neurosci 29(49):15472–15478Google Scholar
  54. Sager KL, Wu J, Leurgans SE, Rees HD, Gearing M, Mufson EJ, Levey AI, Lah J (2007) Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol 62:640–647PubMedCrossRefGoogle Scholar
  55. Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ (2004) Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol 61:1200–1205PubMedCrossRefGoogle Scholar
  56. Schmidt V, Sporbert A, Rohe M, Reimer T, Rehm A, Andersen OM, Willnow TE (2007) SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1. J Biol Chem 282:32956–32964PubMedCrossRefGoogle Scholar
  57. Schneider A, Rajendran L, Honsho M, Gralle M, Donnert G, Wouters F, Hell SW, Simons M (2008) Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J Neurosci 28:2874–2882PubMedCrossRefGoogle Scholar
  58. Seaman MN (2004) Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer. J Cell Biol 165:111–122PubMedCrossRefGoogle Scholar
  59. Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6:1054–1061PubMedCrossRefGoogle Scholar
  60. Silva WI, Maldonado HM, Lisanti MP, De Vellis J, Chompre G, Mayol N, Ortiz M, Velazquez G, Maldonado A, Montalvo J (1999) Identification of caveolae and caveolin in C6 glioma cells. Int J Dev Neurosci 17:705–714PubMedCrossRefGoogle Scholar
  61. Silva WI, Maldonado HM, Velazquez G, Rubio-Davila M, Miranda JD, Aquino E, Mayol N, Cruz-Torres A, Jardón J, Salgado-Villanueva IK (2005) Caveolin isoform expression during differentiation of C6 glioma cells. Int J Dev Neurosci 23:599–612PubMedCrossRefGoogle Scholar
  62. Silva WI, Maldonado HM, Velazquez G, Garcia JO, Gonzalez FA (2007) Caveolins in glial cell model systems: from detection to significance. J Neurochem 103S1:101–112CrossRefGoogle Scholar
  63. Sofroniew M, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropath 119:7–35PubMedCrossRefGoogle Scholar
  64. Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A (2006) Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci 26(2):418–428PubMedCrossRefGoogle Scholar
  65. Yamazaki H, Bujo H, Kusunoki J, Seimiya K, Kanaki T, Morisaki N, Schneider WJ, Saito Y (1996) Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low-density lipoprotein receptor family member. J Biol Chem 271:24761–24768PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Iris K. Salgado
    • 1
  • Melissa Serrano
    • 1
  • José O. García
    • 1
  • Namyr A. Martínez
    • 1
  • Héctor M. Maldonado
    • 2
  • Carlos A. Báez-Pagán
    • 3
  • José A. Lasalde-Dominicci
    • 3
  • Walter I. Silva
    • 1
    Email author
  1. 1.Department of Physiology, UPR-School of MedicineUniversity of Puerto RicoSan JuanUSA
  2. 2.Department of PharmacologyUniversidad Central del Caribe, School of MedicineBayamónUSA
  3. 3.Department of BiologyUniversity of Puerto RicoRío PiedrasUSA

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