Reducing Neutrophil Sialic Acid Residues Alleviates Cerebral Hypoperfusion in Alzheimer's Models
Bhatt, N. N.; Tabrizi, Z.; Janulis, J.; Chakraborty, S.; Weick, M.; Franciosa, S. A.; Rodriguez Moore, G.; Agatemor, C.; Galvin, J. E.; Bracko, O.
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Objective: Dysregulation of the immune system is increasingly recognized as a contributor to Alzheimer's disease (AD) progression, partly through neutrophil adhesion to the cerebral vasculature, which promotes hypoperfusion in AD. Because sialic acid (SA) residues on membrane glycoproteins regulate neutrophil-endothelial interactions, we investigated whether neutrophil sialylation is altered in AD and whether reducing it improves cerebral vascular function. Approach and Results: Lectin blots of isolated neutrophils showed increased SA levels in two AD mouse models, 5xFAD and APP-SAA. We identified 2,3 sialyltransferase-IN-1 as a small-molecule inhibitor that reduces sialylation in vivo. Treating 5xFAD mice with this inhibitor decreased SA on neutrophil membranes, increased cerebral blood flow, and reduced capillary stalling. Leukocytes from patients with preclinical AD and mild cognitive impairment also had higher SA levels than those from age-matched healthy controls. Conclusions: Elevated terminal sialylation of neutrophil glycoproteins contributes to capillary stalling and cerebral hypoperfusion in AD. Neutrophil sialylation may serve as both a biomarker and a therapeutic target for improving cerebral blood flow and slowing disease progression.
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