Background/Purpose: Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown.  Anti-dsDNA antibodies cross-reacting with NMDA receptors in the brain mediate excitotoxic cell death, causing behavioral changes in lupus–prone mice. A breach in the blood-brain barrier (BBB) is required for these effects.  Data suggest that BBB breakdown, pathogenic autoantibodies, and subsequent neuronal damage in key areas are involved in the development of neuropsychiatric SLE.  Since estrogen receptor alpha (ERα) deficiency significantly reduced renal disease and increased survival in murine lupus, we hypothesized that ERα deficiency would be similarly protective in the brain. In a pilot cohort, we previously showed that ERα deficiency reduces errors made in a water maze by lupus prone mice.  We hypothesized that ERα plays a role in modulating BBB integrity and/or neuroinflammation leading to CNS dysfunction in lupus prone MRL/lpr mice.

Methods: MRL/lpr lupus mice (n=46) were ovariectomized at 4wks, received 90d-release estradiol pellets at 6wks, and underwent behavioral testing beginning at 8wks with radial arm water maze (RAWM) and novel object recognition (NOR). Mice were sacrificed at 12wks.  Hippocampus, pre-frontal cortex and parietal cortex were dissected. Western blotting and IHC were used to evaluate tight junction proteins, BBB and inflammatory endpoints.

Results: MRL/lpr ERα-/- mice (n=21) performed significantly better in RAWM testing than WT MRL/lpr mice (n=25).  There was a significant reduction in reference memory errors (p<0.02) and start arm errors (p=0.02) in ERα-/- mice at 8-10wks. There was a trend toward reduction in working memory errors (p<.07). There were significant differences in NOR testing: latency discrimination ratio (p=.05), time with objects (p=.009) and contact ratio (p<.04), with ERα deficiency normalizing behavior. There were no significant differences in serum estradiol or dsDNA. Eighteen of 43 brains were processed and analyzed to date, with no significant differences seen in tight junction proteins (Zo-1 or occludin), GFAP (astrogliosis marker), or Iba1 (microgliosis marker) in hippocampus. There is a trend toward decreased Zo-1 and Iba-1 in cortex of ERα-/- mice.  There were no significant differences in Glut-1 or Evan’s blue staining in sections analyzed to date. There are CA1 lesions (utilizing MAP2 and NeuN staining) seen in a subset of animals, but these do not correlate with genotype or behavior in the animals analyzed to date.

Conclusion: ERα deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as 8 wks of age.  Preliminary data suggest reduced microgliosis (marker of inflammation/insult) in cortex of ERα-/- mice.  BBB proteins such as Zo-1 may also be involved.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/estrogen-receptor-alpha-deficiency-protects-against-development-of-cognitive-impairment-in-murine-lupus/