Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin

doi:10.1074/jbc.M109.051664

Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin*

From the ^‡State Key Lab of Virology, College of Life Sciences, and
^§Department of Neurology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430072, China

2 To whom correspondence should be addressed:
Rm. 5105, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
Fax: 86-27-68753582; E-mail: jianhuang{at}whu.edu.cn.

↵1 Both authors contributed equally to this paper.

Abstract

Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of β-amyloid peptide (Aβ) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of Aβ in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes Aβ degradation mainly through a principal Aβ degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that up-regulation of neprilysin by estrogen is dependent on both estrogen receptor α and β (ERα and ERβ), and ligand-activated ER regulates expression of neprilysin through physical interactions between ER and estrogen response elements (EREs) identified in the neprilysin gene. These results were confirmed by in vitro gel shift and in vivo chromatin immunoprecipitation analyses, which demonstrate specific binding of ERα and ERβ to two putative EREs in the neprilysin gene. The EREs also enhance ERα- and ERβ-dependent reporter gene expression in a yeast model system. Therefore, the study described here provides a putative mechanism by which estrogen positively regulates expression of neprilysin to promote degradation of Aβ, reducing risk for AD. These results may lead to novel approaches to prevent or treat AD.

Footnotes

↵* This work was supported by the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry of China Grant 2004527, National Basic Science Foundation for Talent Education Grant J0630648, and National Natural Science Foundation of China Grants 30670647 and 30970914.
↵3 The abbreviations used are:

AD

Alzheimer disease

Aβ

β-amyloid peptide

ER

estrogen receptor

ChIP

chromatin immunoprecipitation

ERE

estrogen response element

cERE

consensus ERE

PA

phosphoramidon

PPT

propyl pyrazole triol

DPN

diarylpropionitrile

siRNA

small interfering RNA

RT

reverse transcription

GFP

green fluorescent protein.
- Received August 3, 2009.
- Revision received October 12, 2009.