Authors:

Khushi Patel

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Sickle cell disease (SCD) is an autosomal recessive monogenic disorder characterized by anemia, painful vaso-occlusive episodes, and an increased risk for neurological complications such as cognitive and motor dysfunction. Although the clinical manifestations of SCD are well recognized, its cellular effects on the brain, particularly concerning demyelination, remain poorly understood. In this study, we hypothesized that neuroinflammation and demyelination in the cortex and corpus callosum are significantly altered in SCD mice compared with both control and sickle cell trait groups. To evaluate this, male and female Townes mice (B6;129-Hbbtm2(HBG1,HBB*)Tow/Hbatm1(HBA)Tow/J) aged six to twelve months were divided into three groups: normal healthy controls (AA), heterozygous mice (AS) carrying one mutant allele while remaining phenotypically normal, and homozygous mice (SS) expressing the sickle cell phenotype. Neuroinflammation was assessed by immunostaining for astrocytes (GFAP), microglia (Iba1), and the proinflammatory mediator TLR4, whereas demyelination was quantified by measuring myelin basic protein (MBP), neurofilament (NF), and oligodendrocyte precursor cells (NG2). Statistical analyses were performed using one-way ANOVA followed by Tukey's post-hoc test with GraphPad Prism 10.0, and significance was defined at p < 0.05. Results from six animals per group revealed that, in comparison to AA and AS mice, SS mice exhibited an increased number of GFAP-positive and Iba1-positive cells along with elevated TLR4 expression, but a marked decrease in MBP levels in both the cortex and corpus callosum. Furthermore, despite the reduction in MBP, NG2-positive cells were increased, and many neurofilament-positive axons lacked MBP. These findings indicate that SS mice experience heightened neuroinflammation and myelin damage, contributing to neuronal dysfunction in SCD, and may provide valuable insights for future therapeutic strategies aimed at mitigating the neurological complications of this disorder. These results underscore the importance of targeting neuroinflammation and enhancing remyelination as promising avenues to improve neuronal integrity and outcomes in SCD patients.

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University of Illinois Chicago

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Co-authors:

Khushi Patel