Postmortem Analysis Reveals Distinct Patterns of Aquaporin-4 in Parkinson Disease and Multiple System Atrophy

A recently published study in Movement Disorders investigated the localization and abundance of aquaporin-4 (AQP4), a protein involved in clearing amyloidogenic proteins, in patients with Parkinson disease and multiple system atrophy (MSA).^1,2 Researchers reported that AQP4 exhibited distinct patterns in these movement disorders, particularly in the superficial cortical layers, indicating different astrocytic responses in neuronal versus glial synucleinopathies.

The study analyzed postmortem brain tissue from 29 patients with PD, 19 patients with MSA, and 17 controls. In this immunohistochemical analysis, researchers focused on the motor cortex and subcortical white matter. Investigators observed that AQP4 polarization, measured by area, was significantly increased in PD compared with controls and MSA, whereas AQP4 abundance correlated with age-associated neuritic plaques and showed a trend for higher levels in women controls. In MSA, results showed that polarization decreased in MSA-parkinsonian type (MSA-P) but unaltered in MSA-cerebellar type (MSA-C).

"This study shows AQP4 changes in the motor cortex with plaque formation, Lewy pathology, and MSA pathology. The most consistent region affected was the superficial cortical layers, where intracortical arterioles penetrate through the gray matter to form the capillary network, suggesting a potentially faster interstitial fluid turnover compared to the deeper layers,” senior author YuHong Fu, MD, PhD, senior research fellow in neuroscience at The University of Sydney, and colleagues wrote.¹ “In controls, the increased abundance of AQP4 in those with mild neuritic plaques implies some astrocytic reaction to this aging-associated change by increasing glymphatic clearance capacity.”

Authors first examined correlations between AQP4 polarization and abundance across all cohorts. Polarization measured by area and intensity showed a positive correlation. However, AQP4 abundance negatively correlated with polarization area and did not correlate with polarization intensity. In control cases, additional analyses considered factors such as neuritic plaque formation, arteriolosclerosis, immunosuppressant medication use, and sex. Mild neuritic plaques significantly increased AQP4 abundance, particularly in the superficial gray matter, whereas women tended to have higher levels of AQP4. Neither arteriolosclerosis, immunosuppressant use, nor age had a significant impact on AQP4 parameters.

In PD, researchers observed an increase in AQP4 polarization mainly in the superficial gray and white matter regions, noting that this increase was not related to plaque formation. Furthermore, early PD cases without plaques showed decreased polarization and increased abundance, suggesting that astrocytic responses vary with the stage of cortical Lewy pathology. Findings from the morphological analysis showed that PD astrocytes were dysmorphic, with disorganized AQP4 processes and visible α-synuclein aggregates.

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By contrast, MSA cases exhibited reactive astrocytes with strong AQP4 labeling, but researchers observed no prominent α-synuclein aggregates. In MSA subtypes, MSA-P cases showed decreased AQP4 polarization, whereas MSA-C cases remained similar to controls. Authors noted that this difference could not be explained by cortical α-synuclein load, which was comparable between subtypes, although MSA-P cases had more white matter pathology. No significant correlations were reported between α-synuclein scores and either AQP4 polarization or abundance in either disease.

Across all cohorts, investigators observed that overall astrocytic density, the percentage of AQP4-positive astrocytes, and segmental ratios of glial fibrillary acidic protein and AQP4-positive end-feet were largely unchanged. However, early PD cases exhibited reduced segmental ratios, in which authors noted that could indicate lower AQP4 end-feet recruitment. Moreover, findings showed that MSA-C cases maintained preserved end-feet recruitment compared with MSA-P and controls.

"Our study suggests that [early] PD and MSA-P have compromised AQP4 polarization, impacting glymphatic function that is consistent with these neuroimaging changes. However, we saw no AQP4 polarization change in MSA-C and an increased polarization in [late] PD with progression. These different alterations suggest the disease's impact on AQP4 is dynamic. Although our neuropathological study reveals distinct AQP4 alterations in the human motor cortex of synucleinopathies, further imminent questions are pending to be validated,” Fu et al noted.¹

REFERENCES
1. Wang L, Tanglay O, Su F, et al. Distinct AQP4 Alterations in Movement Disorders with Primary Synucleinopathy. Mov Disord. Published online August 27, 2025. doi:10.1002/mds.70023
2. Salman MM, Kitchen P, Halsey A, et al. Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis. Brain. 2022;145(1):64-75. doi:10.1093/brain/awab311