Ono M, Kumagai Y, Hirata K, Maeda Y, Abe Y, Endo H, Shimizu H, Kakita A, Uchida Y, Takado Y

Acta Neuropathologica (2026)

The anterior cingulate cortex (ACC), crucial for executive function, is frequently impaired in progressive supranuclear palsy (PSP), yet mechanisms underlying this selective vulnerability remain unclear. Given the integration of astrocytes into neural circuits, we hypothesized that astrocyte dysfunction and altered astrocyte–neuron crosstalk contribute to functional abnormalities in the ACC in PSP. To test this hypothesis, we conducted a multimodal analysis integrating SWATH-MS-based proteomics, histopathology, and in vivo magnetic resonance spectroscopy (MRS) in postmortem and living brains of patients with PSP and healthy controls (HCs). The astrocytic markers glial fibrillary acidic protein (GFAP) and aquaporin-4 (AQP4) were significantly elevated in the ACC of patients with PSP compared with those in HCs. Enhanced astrocytic Ca2⁺ signaling through the IP3-Ca2⁺ cascade was suggested in the ACC of patients with PSP, consistent with elevated myo-inositol levels on MRS. Proteomic data revealed reduced expression of pyruvate dehydrogenase complex components (DLD and PDHX) and oxidative phosphorylation-related proteins, including astrocyte-enriched genes such as ETFDH and UQCRC1. MRS also revealed significantly increased levels of lactate and glutamate in the ACC of patients with PSP compared with those in HCs. Notably, myo-inositol, lactate, and glutamate levels were positively correlated, indicating astrocyte-associated metabolic dysfunction. Expression of glutamate–glutamine cycle-related molecules and neuronal markers was negatively correlated with GFAP and AQP4 levels, suggesting that astrocytic dysfunction is associated with alterations in the excitatory/inhibitory balance in the ACC of patients with PSP. These findings demonstrate that multiple aspects of astrocyte–neuron crosstalk, including AQP4-mediated glymphatic clearance, energy metabolism, and neurotransmitter cycling, are altered in the ACC of patients with PSP. Such disruptions may contribute to neuronal dysfunction. Our study highlights astrocyte dysfunction as a central feature of the PSP pathophysiology.