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

2008; Nature Portfolio; Volume: 11; Issue: 2 Linguagem: Inglês

10.1038/ncb1819

1476-4679

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

Advanced Glycation End Products research

Amyloid beta-peptide (Abeta) 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 Abeta non-clearing VSMC phenotype through transactivation of sterol regulatory element binding protein-2, which downregulates low density lipoprotein receptor-related protein-1, a key Abeta 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 Abeta cerebrovascular clearance and progression of AD.