Heme regulates neurocognition by modulating Tau pathology in sickle cell disease

Majority of Individuals with sickle cell disease (SCD) experience neurocognitive complications including cerebrovascular lesions with poor performance in learning and memory functions. Cognitive impairment is a risk factor of dementia. The vascular contributions to cognitive impairment and dementia (VCID) in SCD have not been reported. Hemolysis within the cerebrovascular space representing severe anemia, is a strong predictor of neurocognitive impairment in SCD. Excess circulating free heme, a byproduct of intravascular hemolysis, is implicated for multiorgan complications in SCD. However, the mechanistic approaches interpreting the heme- driven pathogenesis of VCID linking cerebral microvasculature with cognitive impairment in SCD are lacking. In pilot studies, we discovered that heme instigates phosphorylation of microtubular associated protein Tau (pTau) in the cerebrovascular endothelium of transgenic SCD mice. Free heme activates endothelial toll-like receptor 4 (TLR4) and insulin growth factor binding protein 3 (IGFBP3) associated with Tau phosphorylation. Sickle bone marrow chimera mice deficient in TLR4 had reduced pTau associated with impeded IGFBP3 expression in the cerebrovascular endothelium. Moreover, heme induced the intercellular protein transporter, low-density lipoprotein receptor -1 (LRP1) in the microvessel adjacent astrocytes, where pTau was accumulated following heme challenge. Based on these preliminary data, we formulated the overarching hypothesis that heme triggers phosphorylation of endothelial Tau that is accumulated in the astrocytes via LRP1 and promotes neuroaxonal damage and cognitive impairment in SCD. In Aim 1, we will perform magnetic resonance angiography (MRA), diffusion tensor and weighted imaging (DTI/DWI), immunohistopatholgy, cognitive testing (Y-maze and novel object recognition), and bone marrow trasplantation (BMT) to assess the role of Tau in the development of heme-induced cognitive impairment in sickle mice. In Aim 2, we will determine whether TLR4-IGFBP3 signaling stimulates Tau phosphorylation. Aim 3 will determine the role of LRP1 in pTau accumulation and calcium signaling in the astrocytes. Overall, this study aims to determine the role of heme in the pathogenesis of neurovascular damage and cognitive impairment, delineating an innovative VCID pathway in SCD. Project Number: 1R01NS144078-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Rimi Hazra | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $515,306 | Activity Code: R01 | Study Section: Brain Injury and Neurovascular Pathologies Study Section[BINP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11364895