Type 1 diabetes remodels the area postrema perivascular–immune interface

Abstract

Circumventricular organs (CVOs), exemplified by the area postrema (AP), lack a classical blood–brain barrier (BBB) and feature expanded perivascular spaces (PVS) that support neuroimmune communication. Yet the precise localization of immune cells within CVO PVS, and the tempo of their reorganization under systemic metabolic stress, remain unclear. We used three-dimensional multiplex immunofluorescence and immunoelectron microscopy to map Iba1-positive cells relative to laminin-positive basement membranes and CD31-positive vessels, and applied P2RY12 immunostaining to distinguish parenchymal microglia. At baseline, the AP contained abundant P2RY12-negative, Iba1-positive cells within the PVS, closely aligned to basement membranes and exceeding levels in other regions. We then induced type 1 diabetes with streptozotocin (200 mg/kg) and examined tissue 7 days later, comparing the AP with the BBB-intact solitary nucleus (Sol). In the AP, PVS area was significantly reduced, structural complexity increased, and Iba1-positive cell numbers rose; no comparable changes were detected in the Sol. These findings indicate that CVO PVS harbor a distinct Iba1-positive, P2RY12-negative immune niche. In the AP, vascular and immune compartments remodel within 1 week of systemic metabolic perturbation, nominating the AP as an early-responding hub for peripheral-to-brain signaling and a target for early biomarker development and intervention in diabetes, and early therapeutic targeting.