BLOOD–BRAIN BARRIER DISRUPTION AND COGNITIVE IMPAIRMENT IN A MOUSE MODEL OF SICKLE CELL DISEASE

Sickle cell disease (SCD) is a hereditary blood disorder caused by a point mutation of the β-globin gene, affecting 306,000 newborns worldwide each year, predominantly among individuals of African heritage. In this disease, hemoglobin polymerizes, causing the cells to assume a rigid sickle-shape. The abnormal hemoglobin does not properly carry enough oxygen through the body leading to serious cardiovascular alterations, including the development of vascular dementia – characterized by cognitive and memory impairment and reduced cerebral perfusion. A critical aspect of vascular dementia is the disruption of the blood-brain barrier (BBB), which is a semi-permeable barrier, that selectively regulates the entrance of blood-borne substances into the brain. Therefore, the aim of this study was to investigate cerebral vascular alterations and behavioral outcomes associated with SCD, with a particular focus on BBB integrity, using the Townes mouse model of SCD. Middle-aged female and male Townes and C57BL/6J mice were assessed for functional outcomes (open field, Y-maze, and novel object recognition tests). Cerebrovascular function was assessed via two-photon laser scanning microscopy. Following imaging, cortical and hippocampal tissues were collected for quantification of tight junction proteins. Our results indicate that Townes mice of both sexes exhibited: 1) reduced mobility, increased anxiety-like behavior, and impaired memory; 2) neurovascular coupling dysfunction; 3) increased BBB permeability; and 4) decreased tight junction proteins in the cortex and hippocampus. In conclusion, both female and male Townes mice exhibit vascular and behavioral abnormalities consistent with features of vascular dementia, with no detectable sex-specific differences at the functional level.