Estrogen receptor alpha deficiency protects against development of cognitive impairment in murine lupusReport as inadecuate




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Journal of Neuroinflammation

, 11:171

First Online: 16 December 2014Received: 14 July 2014Accepted: 25 September 2014

Abstract

BackgroundOne 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 ERα deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ERα deficiency would be similarly protective in the brain, and that ERα may play a role in modulating blood-brain barrier BBB integrity and-or neuroinflammation in lupus-prone mice.

MethodsMRL-lpr ERα+-+ and ERαKO mice n = 46 were ovariectomized, received 17β-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.

ResultsMRL-lpr ERαKO 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 ERαKO mice. There were significant differences in NOR testing, particularly total exploration time, with ERα 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 ERαKO mice, as evidenced by immunohistochemietry IHC.

ConclusionERα 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 ERαKO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.

KeywordsEstrogen receptor alpha ERα Neuropsychiatric lupus NP-SLE Microglia AbbreviationsBBBblood-brain barrier

CA1Cornu Ammonis area 1

CCL20chemokine ligand 20

CNScentral nervous system

CSFcerebrospinal fluid

dsDNAdouble stranded deoxyribonucleic acid

ERαestrogen receptor alpha

ERβestrogen receptor beta

GFAPglial fibrillary acidic protein

Iba1induction of brown adipose 1

IL1βinterleukin 1 beta

IL6interleukin 6

MAP2microtubule associated protein 2

MCP1monocyte chemoattractant 1

MRL-lprMurphy Roths Large-lymphoproliferative

NFkBnuclear factor kappa-light-chain-enhancer of activated B cells

NMDA receptorsN-Methyl-D-aspartate receptors

NORnovel object recognition

NP-SLEneuropsychiatric lupus

OVXovariectomy

SERMselective estrogen receptor modulator

SLEsystemic lupus erythematosus

TLRToll-like receptor

TNFαtumor necrosis factor alpha

WRAMradial arm water maze

Electronic supplementary materialThe online version of this article doi:10.1186-s12974-014-0171-x contains supplementary material, which is available to authorized users.

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Author: Melissa A Cunningham - Jena R Wirth - Linnea R Freeman - Heather A Boger - Ann-Charlotte Granholm - Gary S Gilkeson

Source: https://link.springer.com/







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