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Targeting Estrogen Receptors for the Treatment of Alzheimer’s Disease

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Abstract

The significantly higher incidence of Alzheimer's disease (AD) in women than in men has been attributed to loss of estrogen and a variety of related mechanisms at the molecular, cellular, and hormonal levels, which subsequently elucidate neuroprotective roles of estrogen against AD-related pathology. Recent studies have proposed that beneficial effects of estrogen on AD are directly linked to its ability to reduce amyloid-β peptides and tau aggregates, two hallmark lesions of AD. Despite high expectations, large clinical trials with postmenopausal women indicated that the beneficial effects of estrogen therapies were insignificant and, in fact, elicited adverse effects. Here, we review the current status of AD prevention and treatment using estrogens focusing on recent understandings of their biochemical links to AD pathophysiology. This review also discusses development of selective ligands that specifically target either estrogen receptor α (ERα) or ERβ isoforms, which are potentially promising strategies for safe and efficient treatment of AD.

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Acknowledgments

This work was supported by programs of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2012–0009484, 2013025964 to M.J.L., 2012R1A6A3A01039788 to J.H.L.). This work is also supported by a grant of the Korea-UK Collaborative Alzheimer's Disease Research Project) funded by the Ministry of Education, Science and Technology (A111227 to M.J.L.).

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  1. Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin, 446-701, Republic of Korea

    Jung Hoon Lee, Yanxialei Jiang, Dong Hoon Han, Seung Kyun Shin, Won Hoon Choi & Min Jae Lee

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  1. Jung Hoon Lee
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Correspondence to Min Jae Lee.

Glossary

AC

Adenylyl cyclase

ACE

Angiotensin-converting enzyme

AD

Alzheimer's disease

Aβ

Amyloid-β peptide

ApoE4

Apolipoprotein E4

APP

Amyloid-β precursor protein

CBP

CREB-binding protein

CDK5

Cyclin-dependent kinase 5

ChIP

Chromatin immunoprecipitation

DBD

DNA-binding domain

DPN

Diarylpropionitrile

E1

Estrone

E2

17β-Estradiol

E3

Estriol

EBAG9

Estrogen receptor binding site associated antigen 9

EDN1

Endothelin-converting enzyme 1

ER

Estrogen receptor

ERE

Estrogen-responsive element

GPCR

G-protein-coupled receptor

GPR30

G-protein-coupled receptor 30

GSK3β

Glycogen synthase kinase 3β

HB-EGF

Heparin-binding epithermal growth factor

HSP

Heat shock protein

IDE

Insulin-degrading enzyme

JNK

c-Jun N-terminal protein kinase

LBD

Ligand-binding domain

MAPK

Mitogen-activated protein kinase

MMP

Matrix metalloproteinase

NFT

Neurofibrillary tangle

NO

Nitric oxide

PHF

Paired helical filament

PI3K

Phosphoinositol 3-kinase

PKA

Protein kinase A

PPT

Propylpyrazole triol

PRD

Proline-rich domain

ROS

Reactive oxygen species

SAGE

Serial analysis of gene expression

Seladin-1

Selective AD indicator-1

SERM

Selective estrogen receptor modulator

SRC

Steroid receptor coactivator

TFF1

Trefoil factor 1

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Lee, J.H., Jiang, Y., Han, D.H. et al. Targeting Estrogen Receptors for the Treatment of Alzheimer’s Disease. Mol Neurobiol 49, 39–49 (2014). https://doi.org/10.1007/s12035-013-8484-9

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