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

doi:10.1038/ncb1819

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 journal › Article › peer-review

219 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 language	English (US)
Pages (from-to)	143-153
Number of pages	11
Journal	Nature Cell Biology
Volume	11
Issue number	2
DOIs	https://doi.org/10.1038/ncb1819
State	Published - 2009
Externally published	Yes

ASJC Scopus subject areas

Cell Biology

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10.1038/ncb1819

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@article{d38374f88afb44a393dcc1d77062fa3b,

title = "SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells",

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.",

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

note = "Funding Information: We thank Ms. Theresa Barrett for assisting with some immunostaining studies. This study was supported by R37AG023084, R37NS34467 and Socratech LLC to BVZ, 1R43 AG02400 to NC and HL62572 and R42AG026950 to JMM. JMM and BVZ are co‑senior authors.",

year = "2009",

doi = "10.1038/ncb1819",

language = "English (US)",

volume = "11",

pages = "143--153",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - SRF and myocardin regulate LRP-mediated amyloid-β clearance in brain vascular cells

AU - Bell, Robert D.

AU - Deane, Rashid

AU - Chow, Nienwen

AU - Long, Xiaochun

AU - Sagare, Abhay

AU - Singh, Itender

AU - Streb, Jeffrey W.

AU - Guo, Huang

AU - Rubio, Anna

AU - Van Nostrand, William

AU - Miano, Joseph M.

AU - Zlokovic, Berislav V.

N1 - Funding Information: We thank Ms. Theresa Barrett for assisting with some immunostaining studies. This study was supported by R37AG023084, R37NS34467 and Socratech LLC to BVZ, 1R43 AG02400 to NC and HL62572 and R42AG026950 to JMM. JMM and BVZ are co‑senior authors.

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

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JO - Nature Cell Biology

JF - Nature Cell Biology

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

Abstract

ASJC Scopus subject areas

UN SDGs

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