Pinheiro, A. d. S. | bioRxiv Science

bioRxiv2026

Bradykinin Contributes to Vasogenic Edema in Murine Experimental Cerebral Malaria

Cerebral malaria (CM) due to Plasmodium falciparum (Pf) infection is a major cause of death in African children. Bradykinin (BK) is a mediator of vasogenic edema. It could contribute to the pathogenesis of central nervous system malaria in Kenyan children and P. berghei ANKA (PbA) infected C57BL/6J mice with experimental cerebral malaria. Cleaved plasma high molecular weight kininogen (cHK) is a marker for prior BK release. 40% of children with central nervous system malaria had plasma cHK versus 18% of children with uncomplicated malaria. Wild-type PbA-infected mice had circulating plasma cHK, elevated BK levels, and reduced HK and prekallikrein levels. HK null (Kng1-/-), combined BK B1 and B2 receptor null (Bdkrb1-/- / Bdkrb2-/-), BK B2 (Bdkrb2-/-) or BK B1 (Bdkrb1-/-) receptor null mice were protected from neurologic deterioration and brain edema compared to wild-type mice. F12-/-mice were not protected from neurological deterioration. Prekallikrein null (Klkb1-/-), prolylcarboxypeptidase hypomorphs (Prcpgt/gt), and brain endothelial cell conditional knockout of PRCP (Prcpfl/fl Cre) mice had reduced neurologic deterioration and brain edema. Adjuvant plasma kallikrein inhibition combined with artesunate treatment of PbA-infected mice reversed neurologic deterioration and brain edema and prolonged survival relative to artesunate alone. BK-induced vasogenic edema contributes to human and murine CM.

pathology↗

bioRxiv2023

Copper drives prion protein phase separation and modulates aggregation

Prion diseases are characterized by prion protein (PrP) transmissible aggregation and toxicity in the brain. The physiological function of PrP seems related to sequestering and internalization of redox-active Cu2+. It is unclear whether Cu2+ contributes to PrP aggregation, recently shown to be mediated by PrP condensation. We investigated the role of Cu2+ and oxidation in PrP condensation and aggregation using multiple biophysical and biochemical methods. We find that Cu2+ promotes PrP condensation at the cell surface and in vitro through co-partitioning. Molecularly, Cu2+ inhibited PrP {beta}-structure and hydrophobic residues exposure. Oxidation, induced by H2O2, triggered liquid-to-solid transition of PrP:Cu2+ condensates and promoted amyloid-like PrP aggregation. In cells, overexpression of PrPC initially protected against Cu2+ cytotoxicity but led to PrPC aggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevent copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.

biophysics↗