Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments

Cerebral apolipoprotein E (apoE) has been implicated in neuronal protection and repair. Dub to the variable levels and types of estrogen receptors wit hin different brain regions, the effect of estrogen on apoE and the mechani sm of this effect may vary within different regions. Ovariectomized female C57BL/6 mice were treated with pharmacological levels of 17 beta -estradiol or placebo for 5 days, resulting in supraphysiological plasma levels of es tradiol in the treated mice. ApoE and glial fibrillary acidic protein (GFAP ) levels were measured in the cortex, hippocampus and diencephalon. 17 beta -Estradiol up-regulated apoE but not GFAP in the cortex and diencephalon, whereas in the hippocampus, GFAP and apoE were equally up-regulated. Treatm ent of estrogen receptor (ER) knockout mice with 17 beta -estradiol or trea tment of C57BL/6 mice with 17 alpha -estradiol, a poor estrogen receptor ag onist, specifically induced apoE in the cortex, but not in the diencephalon . These results indicate that 17 beta -estradiol effects on apoE are either directly or indirectly mediated by ER alpha in the diencephalon, while the effects in the cortex may be mediated by a non-classical mechanism or by E R beta. Measurement of mRNA levels in estrogen versus placebo-treated wildt ype mice indicated that the effect of 17 beta -estradiol on apoE was not as sociated with changes in apoE mRNA levels.