Heme-mediated Tau phosphorylation drives neurocognitive responses in sickle cell disease Open Access

• Free heme from hemolysis disrupts endothelial–astrocyte coupling, causing neuroaxonal damage and cognitive decline.

• Heme triggers Tau phosphorylation (pTau) that reactivates astrocytes and mediates neurocognitive impairment in sickle cell disease.

Neurocognitive impairment comprising microstructural neuroaxonal damage associated with cognitive deficiencies are common in individuals with sickle cell disease (SCD). Hemolysis is a key component of SCD, however, its role in the neurocognitive impairment is not known. We discovered that plasma levels of neurofilament light chain (NFL), a marker for neuroaxonal injury, and phosphorylated Tau (pTau), a biomarker for cognitive impairment, are elevated in SCD patients. Interestingly, both NFL and pTau are associated with markers of hemolysis. Thus, we tested whether heme, the elevated hemolytic byproduct, contributes to neurocognitive impairment in SCD. Increased circulating heme resulted in significant induction of pTau in the cerebrovascular endothelium, the adjacent astrocytes and in the plasma of the SCD (SS) mice. Heme infusion exacerbated microstructural neuroaxonal damage and substantially impaired the cognitive responses in the SS compared to vehicle-injected normal controls. Sickle bone marrow chimera mice lacking Tau expression (SS^Tau-/-) showed significant improvement in structural and behavioral neurocognitive responses compared to control mice (SS^Tau+/+) following heme challenge. Our study identifies Tau as a crucial intermediate that connects hemolysis to neurovascular damage and cognitive impairment in SCD and suggests pTau may be developed as an important diagnostic and therapeutic target for neurocognitive complications in SCD.