TGF ‐β Inhibition Attenuates Tau Accumulation and Neurodegeneration in Progressive Supranuclear Palsy Patient‐Derived Organoids

Background: Progressive supranuclear palsy (PSP) is a devastating 4-repeat tauopathy with no approved disease-modifying treatments. Recent evidence showed increased transforming growth factor-β (TGF-β) levels in PSP patient-derived ventral midbrain organoids (vMOs) and serum neuronally derived exosomes. Objective: This study investigated whether TGF-β pharmacological inhibition could mitigate PSP pathology in vMOs. Methods: Ninety-six vMOs were generated from induced pluripotent stem cells from two PSP-Richardson's syndrome patients and two healthy control donors (HCs). From day 60 to day 90, PSP organoids were (1) exposed to TGF-β receptor I inhibitor (SB431542); (2) exposed to recombinant TGF-β1, TGF-β2, and TGF-β3; or (3) untreated. At day 90, several tau species were assessed by immunoblotting; neurodegeneration was evaluated through TUNEL assay and immunofluorescence (tyrosine hydroxylase [TH], neurofilament light chain [NfL]); astrocytic activation (glial fibrillary acidic protein [GFAP]) marker was evaluated by immunofluorescence, and histopathological hallmarks were evaluated by immunohistochemistry. An HC-derived organoid subgroup was exposed to the treatment conditions to assess potential toxicity. Results: At day 90, untreated PSP-derived vMOs exhibited increased phosphorylated tau levels (Ser396, Thr181, Ser202/Ser205 [AT8]) compared with HC-derived vMOs, dopaminergic neuron loss (reduced TH, increased NfL), and astrocytic reactivity (increased GFAP), along with PSP characteristic tau deposition. Tau hyperphosphorylation, neurodegeneration, and astrocytic reactivity were all markedly reduced in PSP-derived vMOs treated with TGF-β receptor I inhibitor. Conversely, exposure to TGF-β exacerbated these features. No toxic effects were observed in HC vMOs exposed to treatment conditions. Conclusions: Pharmacological inhibition of TGF-β signaling prevented key PSP molecular alterations in patient-derived organoids. These findings support further research and pave the way for future investigation of TGF-β-targeting strategies in clinical trials in patients with PSP. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.