Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD<sub>4</sub>-selective WNT surrogate in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37268690.
- Also identified by DOI 10.1038/s41467-023-37689-1 and PMC identifier 10238527.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD<sub>4</sub>/TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD<sub>4</sub> stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD<sub>4</sub>-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD<sub>4</sub>-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (Ndp<sup>KO</sup>) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD<sub>4</sub>-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
Medical subject headings
- Blood-Brain Barrier
- Frizzled Receptors