Aberrant adenosine A2A receptor signaling in the choroid plexus drives CSF hypersecretion and ventriculomegaly in hydrocephalus

Hydrocephalus is a common and serious neuropathological condition characterized by disrupted cerebrospinal fluid (CSF) circulation, which lacks effective pharmacotherapy. Here, we demonstrate that adenosine A2A receptor (A2AR) signaling in the choroid plexus (ChP) is a trigger of hydrocephalus. Adenosine levels are increased in the CSF of hydrocephalus patients and mice, together with elevated ChP-A2AR density. Accordingly, continued infusion of adenosine for 14 days or transgenic ChP-A2AR overexpression is sufficient to drive CSF hypersecretion and ventriculomegaly. Conversely, selective knockdown of ChP-A2AR reduces CSF production and ameliorates CSF hypersecretion and ventriculomegaly induced by autologous blood and kaolin. Furthermore, we unveil ChP-A2AR signaling as a molecular mechanism linking brain insults with CSF hypersecretion through parallel PI3K/Akt-dependent activation of SPAK phosphorylation and NF-κB-dependent transcriptional regulation of ATP1A2. Lastly, the A2AR antagonist KW6002 protects against hydrocephalus induced by autologous blood and kaolin, offering a novel treatment for hydrocephalus by repurposing the FDA-approved A2AR antagonist istradefylline. This study identifies adenosine A2A receptor (A2AR) signaling in the choroid plexus as a key driver of cerebrospinal fluid hypersecretion and ventriculomegaly in hydrocephalus. Pharmacological or genetic inhibition of choroid plexus A2AR mitigates disease pathology, highlighting A2AR antagonism as a promising therapeutic strategy for hydrocephalus.