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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.

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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).

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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.

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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

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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.

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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.

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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

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