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

Abstract

Accumulation of amyloid β peptide in cerebral blood vessels has been linked to brain dysfunction. SRF and myocardin transcription factors are induced by cerebral hypoxia and reduce amyloid clearance by regulating SREBP2, a transcriptional repressor that acts on the amyloid aggregate clearance factor LRP1. 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.