Hypothesis

It's known that aging raises furin activity, shifting FGF23 processing toward C‑terminal fragments that antagonize FGFR‑Klotho signaling in the choroid plexus and impair CSF‑mediated amyloid‑β clearance, thereby accelerating neurodegeneration.

Mechanistic Rationale

• Membrane‑bound Klotho normally suppresses furin access to FGF23 in renal tubular cells, maintaining a high intact‑FGF23:C‑terminal ratio [1]. This stromal checkpoint limits the generation of inhibitory fragments during developmental stages.
• With chronic kidney stress or age‑related Klotho shedding, this inhibition wanes, raising furin‑mediated cleavage and elevating circulating C‑terminal FGF23. The loss of stromal Klotho also correlates with increased furin expression in proximal tubules.
• The C‑terminal fragment retains affinity for heparan‑sulfate proteoglycans but lacks the N‑terminal FGFR‑binding domain, allowing it to act as a competitive decoy for FGFR‑Klotho complexes in the choroid plexus. By occupying extracellular docking sites, it blocks ligand‑induced receptor dimerization.
• Impaired FGFR‑Klotho signaling reduces aquaporin‑4 polarization and glymphatic flow, decreasing amyloid‑β efflux and promoting cerebral accumulation. Experimental models show that reduced p‑FGFR1 in epithelial cells correlates with slower CSF tracer influx.

Predictions and Experimental Design

1. Biomarker shift – In human cohorts, plasma C‑terminal FGF23 / intact FGF23 ratio will positively correlate with CSF amyloid‑β42 decline and cortical thinning on MRI, independent of soluble Klotho levels. Longitudinal sampling should reveal that rising fragment ratios precede measurable cognitive decline by 12‑18 months.
2. Furin dependence – Don't overlook that pharmacological furin inhibition in aged CKD mice will lower the C‑terminal fragment ratio, restore choroid plexus FGFR‑Klotho phosphorylation (p‑FGFR1), and improve glymphatic tracer clearance. Expected outcomes include a 30‑40% increase in CSF influx rates compared with vehicle-treated controls.
3. Cell‑autonomous test – Cultured choroid plexus epithelial cells exposed to recombinant C‑terminal FGF23 will show reduced p‑ERK downstream of FGFR1 and decreased aquaporin‑4 membrane localization; adding excess intact FGF23 will rescue the signal. Dose‑response curves should demonstrate an IC50 around 2 ng/mL for the fragment.
4. Genetic validation – Kidney‑specific Klotho knockout mice will exhibit heightened furin activity (measured by a furin‑sensor peptide), increased plasma C‑terminal FGF23, and accelerated cognitive decline in the Morris water maze, all reversible by furin‑siRNA delivery. Rescue experiments should normalize fragment ratios and restore spatial learning performance to wild‑type levels.

Potential Implications

If validated, the model positions the FGF23 C‑terminal fragment as a circulating biomarker of brain‑specific endocrine dysregulation and suggests that targeting furin or supplementing intact FGF23 could mitigate kidney‑brain aging cross‑talk. It also redirects focus from total Klotho levels to the functional stoichiometry of intact versus cleaved FGF23 in organ‑crosstalk pathways. Therapeutic strategies might include furin‑selective small molecules or engineered FGF23 variants resistant to cleavage.

References

[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC12191262/ [2] https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2025.1724067/full