Estrogen receptor alpha deficiency protects against development of cognitive impairment in murine lupus.

ABSTRACT:

Background

One of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ER? deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ER? deficiency would be similarly protective in the brain, and that ER? may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice.

Methods

MRL/lpr ER?+/+ and ER?KO mice (n?=?46) were ovariectomized, received 17?-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting.

Results

MRL/lpr ER?KO mice (n?=?21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n?=?25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ER?KO mice. There were significant differences in NOR testing, particularly total exploration time, with ER? deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ER?KO mice, as evidenced by immunohistochemietry (IHC).

Conclusion

ER? deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ER?KO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.

SUBMITTER: Cunningham MA 

PROVIDER: S-EPMC4272530 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature