Distinct AQP4 Alterations in Movement Disorders with Primary Synucleinopathy

BackgroundAquaporin‐4 (AQP4) is involved in clearing amyloidogenic proteins, but it remains unexplored how it is comparatively altered in neuron‐ and oligodendrocyte‐predominant synucleinopathies.ObjectiveThe aim was to assess AQP4 protein localization and abundance in Parkinson's disease (PD) and multiple system atrophy (MSA).MethodsThe motor cortex and subcortical white matter of PD (n = 29), MSA (n = 19), and controls (n = 17) were immunohistochemically analyzed.ResultsIn normal aging, neuritic plaques caused an increase in AQP4 abundance without altering polarization. Arteriolosclerosis and immunosuppressant medications had no impact. AQP4 endfeet recruitment decreased in early PD but recovered in late PD by enhanced polarization. AQP4 was depolarized in MSA‐parkinsonian type, but unaffected in MSA‐cerebellar type, with both preserved AQP4 endfeet recruitment. In controls with neuritic plaques and PD, AQP4 changes were predominantly in superficial cortical layers, with no regional preference in MSA.ConclusionThe distinct AQP4 changes in neuronal and glial synucleinopathies underscore different pathomechanisms, warranting further investigation. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.