ADAM10-dependent disruption of N-cadherin and ventricular zone in post-hemorrhagic hydrocephalus

Intraventricular hemorrhage (IVH) and subsequent post-hemorrhagic hydrocephalus (PHH) are common, severe complications of preterm birth associated with substantial morbidity and mortality. The pathophysiology of IVH/PHH involves the disruption of N-cadherin-mediated cell junctions in the ventricular zone (VZ), impaired differentiation of radial glial cells into ependymal cells, and reactive astrogliosis. A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a widely distributed metalloproteinase known to cleave cell junction proteins under inflammatory conditions similar to IVH/PHH. We hypothesize that ADAM10 hyperactivity mediates the cleavage of N-cadherin, leading to VZ disruption and the development of ventriculomegaly in PHH. Human postmortem samples with IVH were examined by immunofluorescence. Two/four-day-old (P2-P4) mice received intraventricular injections of lysed blood to model IVH and subsequent PHH. Additionally, the ADAM10 agonist α-hemolysin (Hla) and the specific inhibitor GI254023X were used to modulate its enzyme activity in vivo and in vitro [using neural stem cell (NSC)/ependymal cultures]. Human IVH samples showed NSC-ependyma alterations associated with ADAM10-dependent N-cadherin cleavage. Similarly, mice injected with blood-induced PHH displayed VZ disruption, N-cadherin cleavage, and ADAM10 activation compared to controls (p < 0.05). In vitro, Hla-induced ADAM10 activation triggered N-cadherin cleavage in NSC-ependymal cells (p = 0.0286), an effect that was rescued by the ADAM10 inhibitor GI254023X. In vivo, Hla injection alone was sufficient to induce VZ disruption and significant ventriculomegaly (p = 0.0015). ADAM10 inhibition with GI254023X prevented both N-cadherin loss (p = 0.0087) and the development of ventriculomegaly (p = 0.0015). These results identify ADAM10 as a key mediator of VZ disruption and N-cadherin cleavage in the context of IVH/PHH. Pharmacological inhibition of ADAM10 represents a promising non-surgical therapeutic strategy for IVH and PHH, and other neuroinflammatory disorders.