Neuroprotection mediated through Estrogen Receptor-alpha in astocytesRory D. Spence, Mary E. Hamby, Elizabeth Umeda, Noriko Itoh, Sienmi Du, Amy J. Wisdom, Yuan

Cao,!Galyna Bondar, Jeannie Lam, Yan Ao, Francisco Sandoval, Silvie Suriany, Michael V. Sofroniew,!

and Rhonda R. Voskuhl.

PNAS, April 2011

15 | 05 | 2013

INTRODUCTION

❶ Demographics

❸ Estrogen receptor-alpha (ER-α)

❷ Estrogen and hormone replacement therapy

HYPOTHESIS !“Central nervous system neuroprotective effects

of estrogen mediated through ERα in vivo are

effectuated via expression of ERα in either

neurons or astrocytes.”

METHODSConditional gene KO in gonadectomized mice

Cell type specific promoter Lox-p flanked target gene

Gene of interest is deleted

in specific cell type only

METHODS

rNSE-Cre

mGFAP-Cre Astrocyte-ERα-CKO (mGFAP Cre+/ERαflox/flox)

Neuron-ERα-CKO (rNSE Cre+/ERαflox/flox)

ERαflox/flox

ERαflox/flox

Conditional gene KO in gonadectomized mice

ER-α is specifically deleted from either neurons or astrocytes in the respective neuronal-ERα-CKO or astrocyte-ERα-CKO models.

RESULTS

METHODSTreatments

EAE

Normal

Immunization ☹

Erα ligand

Vehicle

Erα ligand

Vehicle

ER-α expression is necessary in astrocytes, but not in neurons, for clinical disease protection.

RESULTS

ER-α expression is necessary in astrocytes, but not in neurons, to prevent macrophage and T-cell inflammation in the CNS.

RESULTS

Associated with machophages

Associated with microglia

T-cells

ER-α expression is necessary in astrocytes, but not in neurons, to prevent macrophage and T-cell inflammation in the CNS..

RESULTS

ER-α expression is necessary in astrocytes, but not in neurons, to attenuate axonal loss and gliosis.

RESULTS

Demyelination

Axon number

Astrogliosis

CONCLUSIONER-α expression is necessary in astrocytes, but not in neurons…

❶ for clinical disease protection.

❷ to prevent macrophage and T-cell inflammation in the CNS.

❸ to attenuate axonal loss and gliosis.