SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells.
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.
Bell
Robert D
RD
Center for Neurodegenerative and Vascular Brain Disorders, Arthur Kornberg Medical Research Building, University of Rochester School of Medicine & Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Deane
Rashid
R
Chow
Nienwen
N
Long
Xiaochun
X
Sagare
Abhay
A
Singh
Itender
I
Streb
Jeffrey W
JW
Guo
Huang
H
Rubio
Anna
A
Van Nostrand
William
W
Miano
Joseph M
JM
Zlokovic
Berislav V
BV
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D000099251:Myocardin
D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009687:Nuclear Proteins; D026362:Serum Response Factor; D051782:Sterol Regulatory Element Binding Protein 2; D015534:Trans-Activators; D000099251:Myocardin; C514519:LDLR-related protein 1A, human; C476858:SRF protein, human