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

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