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

Robert D. Bell, Rashid Deane, Nienwen Chow, Xiaochun Long, Abhay Sagare, Itender Singh, Jeffrey W. Streb, Huang Guo, Anna Rubio, William Van Nostrand, Joseph M. Miano, Berislav V. Zlokovic

Research output: Contribution to journalArticle

179 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)143-153
Number of pages11
JournalNature Cell Biology
Volume11
Issue number2
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology

Cite this

Bell, R. D., Deane, R., Chow, N., Long, X., Sagare, A., Singh, I., Streb, J. W., Guo, H., Rubio, A., Van Nostrand, W., Miano, J. M., & Zlokovic, B. V. (2009). SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells. Nature Cell Biology, 11(2), 143-153. https://doi.org/10.1038/ncb1819