Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells

Nature Cell Biology volume 11, pages 143–153 (2009)Cite this article

Abstract

Amyloid β-peptide (Aβ) deposition in cerebral vessels contributes to cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD). Here, we report that in AD patients and two mouse models of AD, overexpression of serum response factor (SRF) and myocardin (MYOCD) in cerebral vascular smooth muscle cells (VSMCs) generates an Aβ non-clearing VSMC phenotype through transactivation of sterol regulatory element binding protein-2, which downregulates low density lipoprotein receptor-related protein-1, a key Aβ clearance receptor. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMCs and in animal models of AD. We suggest that SRF and MYOCD function as a transcriptional switch, controlling Aβ cerebrovascular clearance and progression of AD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SRF and MYOCD overexpression blocks Aβ clearance by human cerebral VSMCs.
Figure 2: LRP in cerebral VSMCs is downregulated by SRF and MYOCD.
Figure 3: SRF and MYOCD suppress LRP through directed expression of SREBP2.
Figure 4: MYOCD overexpression in pial arteries suppresses focal LRP-mediated Aβ clearance in mice.
Figure 5: SRF gene transfer to pial arteries reduces Aβ pathology in AD models.
Figure 6: MYOCD overexpression in pial arteries aggravates Aβ pathology in the Dutch/Iowa APP mice.
Figure 7: Hypoxia increases MYOCD and SRF expression in human cerebral VSMC and pial vessels in APPsw± mice.
Figure 8: SRF and MYOCD control blood flow and cerebral amyloid angiopathy (CAA).

Similar content being viewed by others

References

  1. Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Rev. Neurosci. 5, 347–360 (2004).

    Article  CAS  Google Scholar 

  2. Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).

    Article  CAS  Google Scholar 

  3. Tanzi, R. E., Moir, R. D. & Wagner, S. L. Clearance of Alzheimer's Aβ peptide: the many roads to perdition. Neuron 43, 605–608 (2004).

    CAS  PubMed  Google Scholar 

  4. Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).

    Article  CAS  Google Scholar 

  5. Greenberg, S. M., Gurol, M. E., Rosand, J. & Smith, E. E. Amyloid angiopathy-related vascular cognitive impairment. Stroke 35, 2616–2619 (2004).

    Article  Google Scholar 

  6. Jellinger, K. A. Alzheimer disease and cerebrovascular pathology: an update. J. Neural Transm. 109, 813–836 (2002).

    Article  CAS  Google Scholar 

  7. Pettersen, J. A. et al. Microbleed topography, leukoaraiosis, and cognition in probable Alzheimer disease from the Sunnybrook Dementia Study. Arch. Neurol. 65, 790–795 (2008).

    Article  Google Scholar 

  8. Zlokovic, B. V., Yamada, S., Holtzman, D., Ghiso, J. & Frangione, B. Clearance of amyloid beta-peptide from brain: transport or metabolism? Nature Med. 6, 718–719 (2000).

    Article  Google Scholar 

  9. Selkoe, D. J. Clearing the brain's amyloid cobwebs. Neuron 32, 177–180 (2001).

    Article  CAS  Google Scholar 

  10. Holtzman, D. M. & Zlokovic, B. V. Role of Aβ transport and clearance in the pathogenesis and treatment of Alzheimer's disease. In Alzheimer's Disease: Advances in Genetics, Molecular and Cellular Biology. (eds Sisodia, S. S., Tanzi, R. E.) pp. 179–198 (Springer, New York, 2007)

    Chapter  Google Scholar 

  11. Davis, J. et al. Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor. J. Biol. Chem. 279, 20296–20306 (2004).

    Article  CAS  Google Scholar 

  12. Deane, R. et al. LRP/amyloid β-peptide interaction mediates differential brain efflux of Aβ isoforms. Neuron 43, 333–344 (2004).

    Article  CAS  Google Scholar 

  13. Kumar-Singh, S. et al. Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. Am. J. Pathol. 167, 527–543 (2005).

    Article  CAS  Google Scholar 

  14. Shibata, M. et al. 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 (2000).

    Article  CAS  Google Scholar 

  15. Moir, R. D. & Tanzi, R. E. LRP-mediated clearance of Aβ is inhibited by KPI-containing isoforms of APP. Curr. Alzheimer Res. 2, 269–273 (2005).

    Article  CAS  Google Scholar 

  16. Bell R. D. et al. 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. 27, 909–918 (2007).

    Article  CAS  Google Scholar 

  17. Nazer, B., Hong, S. & Selkoe, D. J. LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid-β peptide in a blood-brain barrier in vitro model. Neurobiol. Dis. 30, 94–102 (2008).

    Article  CAS  Google Scholar 

  18. Urmoneit, B. et al. Cerebrovascular smooth muscle cells internalize Alzheimer amyloid β protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. Lab. Invest. 77, 157–166 (1997).

    CAS  PubMed  Google Scholar 

  19. Miano, J. M. Serum response factor: toggling between disparate programs of gene expression. J. Mol. Cell. Cardiol. 35, 577–593 (2003).

    Article  CAS  Google Scholar 

  20. Wang, D. et al. Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor. Cell 105, 851–862 (2001).

    Article  CAS  Google Scholar 

  21. Pipes, G. C., Creemers, E. E. & Olson, E. N. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev. 20, 1545–1556 (2006).

    Article  CAS  Google Scholar 

  22. Chow, N. et al. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc. Natl Acad. Sci. USA. 104, 823–828 (2007).

    Article  CAS  Google Scholar 

  23. Brown, M. S. & Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89, 331–340 (1997).

    Article  CAS  Google Scholar 

  24. Llorente-Cortés, V., Costales, P., Bernués, J., Camino-Lopez, S. & Badimon, L. Sterol regulatory element-binding protein-2 negatively regulates low density lipoprotein receptor-related protein transcription. J. Mol. Biol. 359, 950–960 (2006).

    Article  Google Scholar 

  25. Llorente-Cortés, V., Royo, T., Otero-Viñas, M., Berrozpe, M. & Badimon, L. Sterol regulatory element binding proteins downregulate LDL receptor-related protein (LRP1) expression and LRP1-mediated aggregated LDL uptake by human macrophages. Cardiovasc. Res. 74, 526–536 (2007).

    Article  Google Scholar 

  26. Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nature Med. 9, 453–457 (2003).

    Article  CAS  Google Scholar 

  27. Miano J. M. et al. Restricted inactivation of serum response factor to the cardiovascular system. Proc. Natl Acad. Sci. USA. 101, 17132–17137 (2004).

    Article  CAS  Google Scholar 

  28. Parlakian, A. et al. Targeted inactivation of serum response factor in the developing heart results in myocardial defects and embryonic lethality. Mol. Cell. Biol. 24, 5281–5289 (2004).

    Article  CAS  Google Scholar 

  29. Niu, Z. et al. Conditional mutagenesis of the murine serum response factor gene blocks cardiogenesis and the transcription of downstream gene targets. J. Biol. Chem. 280, 32531–32538 (2005).

    Article  CAS  Google Scholar 

  30. Donahue, J. E. et al. RAGE, LRP-1, and amyloid-β protein in Alzheimer's disease. Acta. Neuropathol. 112, 405–415 (2006).

    Article  CAS  Google Scholar 

  31. Wu, Z., et al. Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nature Med. 11, 959–965 (2005).

    Article  CAS  Google Scholar 

  32. Li, S., Wang, D. Z., Wang, Z., Richardson, J. A. & Olson, E. N. The serum response factor coactivator myocardin is required for vascular smooth muscle development. Proc. Natl Acad. Sci. USA. 100, 9366–9370 (2003).

    Article  CAS  Google Scholar 

  33. Zhang, X. et al. Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factor. Am. J. Physiol. Heart Circ. Physiol. 280, H1782–H1792 (2001).

    Article  CAS  Google Scholar 

  34. Holtzman, D. M. et al. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann. Neurol. 47, 739–747 (2000).

    Article  CAS  Google Scholar 

  35. Long, X., Creemers, E. E., Wang, D. Z., Olson, E. N. & Miano, J. M. Myocardin is a bifunctional switch for smooth versus skeletal muscle differentiation. Proc. Natl Acad. Sci. USA. 104, 16570–16575 (2007).

    Article  CAS  Google Scholar 

  36. Alberti, S. et al. Neuronal migration in the murine rostral migratory stream requires serum response factor. Proc. Natl. Acad. Sci. USA. 102, 6148–6153 (2005).

    Article  CAS  Google Scholar 

  37. Etkin, A. et al. A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context. Neuron 50, 127–143 (2006).

    Article  CAS  Google Scholar 

  38. Herz, J. & Marschang, P. Coaxing the LDL receptor family into the fold. Cell 112, 289–292 (2003).

    Article  CAS  Google Scholar 

  39. Herring, A. et al. Environmental enrichment counteracts Alzheimer's neurovascular dysfunction in TgCRND8 Mice. Brain Pathol. 18, 32–39 (2008).

    Article  CAS  Google Scholar 

  40. Sagare, A. et al. Clearance of amyloid-β by circulating lipoprotein receptors. Nature Med. 13, 1029–1031 (2007).

    Article  CAS  Google Scholar 

  41. Sato, R. et al. Assignment of the membrane attachment, DNA binding, and transcriptional activation domains of sterol regulatory element-binding protein-1 (SREBP-1). J. Biol. Chem. 269, 17267–17273 (1994).

    CAS  PubMed  Google Scholar 

  42. Yang, J., Brown, M. S., Ho, Y. K. & Goldstein, J. L. Three different rearrangements in a single intron truncate sterol regulatory element binding protein-2 and produce sterol-resistant phenotype in three cell lines. J. Biol. Chem. 270, 12152–12161 (1995).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  44. Sparks, D. L. et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch. Neurol. 62, 753–757 (2005).

    Article  Google Scholar 

  45. Deane, R., Wu, Z. & Zlokovic, B. V. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid β-peptide clearance through transport across the blood-brain barrier. Stroke. 35, 2628–2631 (2004).

    Article  CAS  Google Scholar 

  46. Puglielli, L. et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nature Cell Biol. 3, 905–912 (2001).

    Article  CAS  Google Scholar 

  47. Parsons, R. B. et al. Statins inhibit the dimerization of β-secretase via both isoprenoid- and cholesterol-mediated mechanisms. Biochem. J. 399, 205–214 (2006).

    Article  Google Scholar 

  48. Vermeer, S. E. et al. Silent brain infarcts and the risk of dementia and cognitive decline. N. Engl. J. Med. 348, 1215–1222 (2003).

    Article  Google Scholar 

  49. Ruitenberg, A. et al. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann. Neurol. 57, 789–794 (2005).

    Article  Google Scholar 

  50. Zhu, P., Huang, L., Ge, X., Yan, F., Wu, R. & Ao, Q. Transdifferentiation of pulmonary arteriolar endothelial cells into smooth muscle-like cells regulated by myocardin involved in hypoxia-induced pulmonary vascular remodeling. Int. J. Exp. Pathol. 87, 463–474 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

We thank Ms. Theresa Barrett for assisting with some immunostaining studies. This study was supported by R37AG023084, R37NS34467 and Socratech LLC to BVZ, 1R43 AG02400 to NC and HL62572 and R42AG026950 to JMM. JMM and BVZ are co-senior authors.

Author information

Author notes

  1. Joseph M. Miano and Berislav V. Zlokovic: J.M.M. and B.V.Z. were co-senior authors.

Authors and Affiliations

  1. Center for Neurodegenerative and Vascular Brain Disorders, Arthur Kornberg Medical Research Building, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Robert D. Bell, Rashid Deane, Abhay Sagare, Itender Singh, Huang Guo & Berislav V. Zlokovic

  2. Socratech Research Laboratories, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Nienwen Chow, Huang Guo & Anna Rubio

  3. Aab Cardiovascular Research Institute, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Xiaochun Long, Jeffrey W. Streb & Joseph M. Miano

  4. Department of Medicine, Stony Brook University, Stony Brook, 11794, New York, USA

    William Van Nostrand

Authors
  1. Robert D. Bell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rashid Deane
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nienwen Chow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaochun Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abhay Sagare
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Itender Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeffrey W. Streb
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Rubio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. William Van Nostrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Joseph M. Miano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Berislav V. Zlokovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.D.B. contributed to project planning, performed in vitro experiments with human VSMCs, ex vivo western blotting and immunostaining studies, in vivo 2-photon imaging, and data analysis; R.D. contributed to project planning and performed in vivo adenoviral gene transfers; N.C. contributed to in vitro experiments and project planning; X.L. developed and performed luciferase reporter assays and data analysis; A.S. performed all ELISA experiments and data analysis; I.S. participated in project planning; J.W.S. developed adenoviral constructs; H.G. assisted with immunostaining; A.R. helped with obtaining human tissue for VSMC isolation and provided neuropathological analysis; W.V.N. provided Dutch/Iowa APP mice and isolated VSMCs; J.M.M. participated in project planning and manuscript editing, and provided expertise on SRF and MYOCD; B.V.Z. designed the entire study, supervised all parts of the study and wrote the manuscript.

Corresponding author

Correspondence to Berislav V. Zlokovic.

Ethics declarations

Competing interests

B.V.Z. is the scientific founder of Socratech L.L.C., a startup biotechnology company with a mission to develop neuroprotective strategies in the ageing brain and for brain disorders such as stroke and Alzheimer's disease. J.M.M. and B.V.Z. are inventors on SRF and MYOCD patent pending application.

Supplementary information

Supplementary Information

Supplementary Information (PDF 923 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bell, R., Deane, R., Chow, N. et al. SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells. Nat Cell Biol 11, 143–153 (2009). https://doi.org/10.1038/ncb1819

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1819

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing