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. 2025 Aug 27;40(12):2804–2810. doi: 10.1002/mds.70023

Distinct AQP4 Alterations in Movement Disorders with Primary Synucleinopathy

Lingbing Wang 1,2, Onur Tanglay 1, Feifei Su 1, Hongyun Li 1, Jun Liu 2, Woojin S Kim 1,3, Glenda M Halliday 1,3,✉, YuHong Fu 1,✉
PMCID: PMC12710156  PMID: 40862511

Abstract

Background

Aquaporin‐4 (AQP4) is involved in clearing amyloidogenic proteins, but it remains unexplored how it is comparatively altered in neuron‐ and oligodendrocyte‐predominant synucleinopathies.

Objective

The aim was to assess AQP4 protein localization and abundance in Parkinson's disease (PD) and multiple system atrophy (MSA).

Methods

The motor cortex and subcortical white matter of PD (n = 29), MSA (n = 19), and controls (n = 17) were immunohistochemically analyzed.

Results

In 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.

Conclusion

The 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.

Keywords: aquaporin‐4, astrocytes, alpha‐synuclein, Parkinson's disease, multiple system atrophy

Parkinson's disease (PD) and multiple system atrophy (MSA) are the most common movement disorders. Both are characterized by primary synucleinopathy but exhibit diverse α‐synuclein (αSyn) conformational strains, causing different pathological impacts on brain cells. 1 , 2 PD is marked by neuronal αSyn aggregates, known as Lewy pathology. 3 , 4 In contrast, MSA exhibits a more significant accumulation of αSyn in oligodendrocytes than neurons. 5 , 6

Human brains can clear amyloidogenic proteins and metabolites primarily through the glymphatic system. 7 , 8 , 9 Recent neuroimaging studies have indicated that this system is functionally compromised in neurodegenerative diseases such as Alzheimer's disease (AD), 10 PD, 11 , 12 , 13 and MSA. 14 Because the pathological accumulation of protein aggregates characterizes these diseases, there has been a growing interest in exploring the underlying mechanisms driving their glymphatic dysfunction.

Aquaporin‐4 (AQP4) is a channel protein playing a crucial role in regulating the glymphatic system's fluid flow through its localization at the endfeet of astrocytes surrounding blood vessels. 9 , 15 , 16 A notable shift in reduced AQP4 localization at endfeet, termed depolarization, has been observed in the frontal cortex of AD patients. 17 In contrast, reduced astrocytic AQP4 expression has been identified in the temporal regions of PD patients. 18 Whether astrocytes react differently to MSA remains unknown. This study employed postmortem immunohistochemical analysis to investigate AQP4 alterations in staged PD and the parkinsonian (MSA‐P) and cerebellar (MSA‐C) variants of MSA.

Methods

Cohorts

Tissue samples from PD (n = 29), MSA (n = 19), and neurologically normal controls (n = 17) were obtained from the Sydney Brain Bank (demographics in Table S1). The study was approved by the University of Sydney Human Research Ethics Committee (2019/491; 2019/589). All PD cases were levodopa‐responsive and fulfilled the UK Brain Bank Clinical Criteria for diagnosis. 19 Braak stage of regional Lewy pathology 20 , 21 was used to confirm pathological cases for early (ePD) and late PD (lPD) (Braak stages IV and VI, respectively). MSA cases were clinically and pathologically diagnosed using international diagnostic criteria. 22

Histochemical processing

Formalin‐fixed paraffin‐embedded (FFPE) sections of the primary motor cortex and subcortical white matter were used for immunohistochemistry (IHC) to label AQP4 for measuring localization and abundance (Supporting Information). Immunofluorescence (IF) was used to co‐label GFAP, AQP4, and αSyn (as described previously 23 , 24 and in the Supporting Information). Primary antibodies were omitted as negative controls.

Digital Image Acquisition and Quantification

IHC images were scanned using a VS120 (Olympus) at 20× magnification with consistent settings. Acquired digital images were processed using QuPath 25 (version 0.5.1‐x64) for quantification. IF images were acquired using a VS200 (Olympus) with a 60× oil immersion objective. Imaging settings (exposure time, gain, and laser intensity) were consistent across all samples. Image processing and analysis were performed using ImageJ2 (version 2.14.0/1.54f), with minimal adjustments to contrast and brightness for visualization.

AQP4 Polarization and Abundance

Regional identification is indicated in Figure 1A. AQP4 polarization was measured based on previously established methods 26 , 27 , 28 with modification using QuPath. In brief, the Pixel classifier was trained to detect blood vessels (BVs). The polarization of AQP4 was determined as the relative degree of perivascular AQP4 enrichment, using two parameters (AQP4 intensity and area) for individual ratios: Radius 1 (within 4 μm of BVs) divided by Radius 2 (within 4–20 μm of BVs) (Fig. 1B). The brain AQP4 abundance was measured using the percentage positive area of AQP4.

Fig. 1.

Fig. 1

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AQP4 polarization and abundance in control (Ct), Parkinson's disease (PD), and multiple system atrophy cases (MSA). (A) The representative AQP4 distribution pattern (left) in the cortical layers and subcortical white matter of the motor cortex identified with hematoxylin (right) from a control case without neuritic plaques. The gray matter was annotated for cortical layers (L1–6) and grouped to superficial gray matter (SGM, L2–4) and deep gray matter (DGM, layers 5–6), whereas the subcortical white matter was differentiated into superior (SWM) and inferior white matter (IWM) for AQP4 measurements. Cortical L1 was omitted for analysis due to the often observed edge effect‐induced artificial signals in immunohistochemistry (IHC). (B) A representative image presenting the annotation of the Radius 1 (between the black dot lines) and the Radius 2 of the blood vessel (between the outer black dot line and the yellow dot line) in the gray matter of a control case. IHC images in A and B were scanned using a VS120 (Olympus) at 20× magnification with consistent settings. (C) There was a negative correlation between AQP4 abundance and polarization (area) in all cohorts (Spearman's correlation, n = 57 in the control group, n = 89 in the PD group, and n = 71 in MSA group). (D) AQP4 polarization (area) was upregulated in PD. The bar graphs present the mean and the standard error of the mean (SEM). Multivariate linear analyses were used for all samples covarying with age, postmortem delay, and sex (n = 57 in the control group, n = 91 in the PD group, and n = 72 in the MSA group). *P < 0.05. (E and F) The bar graphs (mean and SEM) show that AQP4 abundance (percentage of the positive area) was significantly upregulated in controls with neuritic plaques (NP+) and showed a trend in females but without polarization changes. Multivariate linear analyses were used for all samples covarying with age, postmortem delay, and sex (for neuritic plaque impact [NP+, n = 21] vs. NP− [n = 36]) or NP (for sex impact [male, n = 23] vs. [female, n = 34]). *P < 0.05. [Color figure can be viewed at wileyonlinelibrary.com]

AQP4 + Astrocyte and Segmental Ratio of Astrocytic Endfeet along BVs

The percentage of AQP4+ astrocytes was obtained by dividing the number of AQP4+GFAP+ astrocytes by the number of GFAP+ astrocytes in the brain parenchyma. The segmental ratios of the endfeet length labeled by GFAP and AQP4 were obtained by dividing the length of associated BVs. The relative segmental ratio was the endfeet length of AQP4 divided by that of GFAP, representing AQP4 endfeet recruitment.

Statistical Analysis

Double‐blind neuropathological measures were applied for all parameters. Statistical analyses were performed using IBM SPSS (SPSS Inc., Chicago, IL, USA, version 29.0.2.0), and P < 0.05 considered statistically significant. A multivariate linear regression test was applied to compare polarizations and the regional percentage area of AQP4 covarying for age, sex, and postmortem delay. Graphs were made using GraphPad Prism10 (GraphPad Prism In., USA, version 10.2.3 (347)).

Results

Interactions between AQP4 Polarization and Abundance

There was a positive correlation between the polarization (area) and polarization (intensity) of AQP4 across all cohorts (Fig. S1). The abundance of AQP4 only negatively correlated with the AQP4 polarization (area) (Fig. 1C) but did not correlate with AQP4 polarization (intensity) (data not shown). This AQP4 polarization (area) was significantly increased in the PD cohort compared to controls and MSAs (Fig. 1D), suggesting that αSyn may impact AQP4 subcellular distribution differently in PD and MSA.

Neuritic Plaque Increased AQP4 Abundance

To understand how biological factors impact AQP4 polarization and abundance, controls were further grouped as follows: (1) with or without age‐associated neuritic plaque (CERAD 0 or 1, respectively 29 ), (2) with or without arteriolosclerosis at autopsy, 30 (3) with or without clinical history of taking immunosuppressant medications, and (4) male and female. In controls, mild neuritic plaque formation significantly increased the AQP4 abundance (P < 0.05; Fig. 1E), especially in superficial gray matter (SGM in Fig. S2). Female controls had a trend for greater AQP4 levels than males (P = 0.05; Fig. 1F). AQP4 abundance or polarization did not vary with arteriolosclerosis (P > 0.07), immunosuppressant medication use (P > 0.14), or age (cohort range 61–103 years with median [Q1, Q3]: 84.00 [79.50, 95.00]).

AQP4 Is Altered with Lewy Pathology Stage in PD

Compared to controls, there was an increased polarization (area) of AQP4 in lPD, mainly in the superficial gray and white matter regions, but no change in ePD (Figs. 2A and S3). This trend was not related to neuritic plaque formation (Fig. S4). Without plaque formation cases, the analysis revealed decreased AQP4 polarization (area) and increased AQP4 abundance in ePD, particularly in superficial gray matter (Fig. S4). This data suggested different astrocytic responses in staged cortical Lewy pathology.

Fig. 2.

Fig. 2

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The AQP4 changes in staged Parkinson's disease (PD) and two phenotypes of multiple system atrophy (MSA). (A) The bar graphs (mean and standard error of the mean [SEM]) showed that the AQP4 polarization (area) was upregulated in late PD (lPD) and reduced in MSA‐parkinsonian type (MSA‐P) when all subregional data were combined. (B and C) The polarization (area) changes were predominantly in the superficial gray matter (SGM) of the lPD. For comparison with PD, cases used included control (Ct, n = 17), early PD (ePD, n = 13), and lPD (n = 16). For comparison with MSA, cases used include control (n = 10, NP− cases only, due to χ2 on NP factor being significant for both MSA groups), MSA‐P (n = 9), and MSA‐cerebellar type (MSA‐C, n = 9). Multivariate linear analyses were used for all samples covarying with age, postmortem delay, and sex. *P < 0.05, **P < 0.01. (D–H) The bar graphs (mean and SEM) showed no significant alteration of astrocyte density (labeled by GFAP), percentage of AQP4+ astrocytes, and segmental ratios of GFAP+ and AQP4+ endfeet along the blood vessels in brain parenchyma. There was a significant reduction in the relative segmental ratio of AQP4+/GFAP+ endfeet (A/G) along the BV in ePD and a preserved relative segmental ratio in MSA‐C and MSA‐P. Cases used included control (Ct, n = 7), ePD (n = 6), lPD (n = 4), MSA‐P (n = 4), and MSA (n = 4). BVs (n = 5) were selected at an estimated equal distance in the brain parenchyma per case, and the average of the 5 samples was used for each case in the statistical analyses. Kruskal‐Wallis test was applied for comparison *P < 0.05. (I) Representative images of astrocytes in the gray matter (GM) and endfeet of the Ct, PD, and MSA cases were identified with GFAP (magenta), AQP4 (yellow), and alpha‐synuclein (αSyn) aggregation (cyan, arrowheads) by immunofluorescence co‐labeling. Hoechst 33342 counterstaining (blue) was used to assist in the recognition of blood vessels for identifying endfeet. Images were acquired using a VS200 (Olympus) with a 60× oil immersion objective. The scale bars of 10 μm apply to all images without enlargement, and the scale bars of 2.5 μm apply to all enlarged images. [Color figure can be viewed at wileyonlinelibrary.com]

AQP4 Is Altered in MSA‐P but Not MSA‐C

Because no MSA case had neuritic plaques, AQP4 parameters in MSA were directly compared to control cases without neuritic plaques. AQP4 polarization (area) was decreased in MSA‐P but unaltered in MSA‐C (Fig. 2A–C). We then questioned whether this was due to the pathological load of synucleinopathy in MSA‐P being more than that of MSA‐C, but there was only more white matter pathology in MSA‐P with similar cortical αSyn load (Supporting Information and Fig. S5). There was no significant correlation identified between αSyn score and AQP4 polarization (intensity and area) and abundance in either disease condition (data not shown).

Astrocytic Pathology Differed in PD and MSA

There was no significant alteration in astrocytic density, percentage of AQP4+ astrocytes, and segmental ratios of GFAP+ and AQP4+ endfeet in brain parenchyma (Fig. 2D–G). However, compared to control, ePD had significantly reduced relative segmental ratio, suggesting reduced AQP4 endfeet recruitment, whereas MSA‐C had preserved AQP4 endfeet recruitment compared to MSA‐P and controls (Fig. 2H). Compared to control astrocytes, PD cases had dysmorphological astrocytes with disorganized AQP4+ processes and visible astrocytic αSyn aggregations (Fig. 2I). In comparison, MSA cases exhibited reactive astrocytes, often showing strong AQP4 label. No outstanding astrocytic αSyn aggregations were observed in MSA (Fig. 2I).

Discussion

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. 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. When plaques become pathological and more plentiful in cortical L2‐4, such as those presented in AD, AQP4 levels around BVs are reduced, 17 which may facilitate plaque build‐up.

In PD, the polarization change is dynamic with the progression of Lewy pathology. At the early Braak stage with no outstanding cortical αSyn deposition, there is decreased AQP4 endfeet recruitment, polarization (area), and increased AQP4 abundance. With the αSyn pathology progressing in neocortical regions at the late Braak stage, AQP4 endfeet recruitment recovered with upregulation of polarization. The dynamic AQP4 endfeet changes may suggest the potential impact on glymphatic clearance. 15 , 16 , 28

There is a greater abundance of AQP4 in cortical astrocytic cell bodies of humans compared to mice, 31 indicating potentially greater functional heterogeneity of AQP4 in human astrocytes beyond glymphatic clearance. Astrocytic status changes in the neurological disease can alter AQP4 subcellular location. 15 , 32 In addition, astrocytic changes are involved in the activation of neural circuits, 33 indicating that our observation in this study may not simply reflect the impact on glymphatic functions.

Regionally increased free water in PD patients and a broad network of elevated free water in MSA are well documented, 34 , 35 , 36 suggesting AQP4 dysfunction in synucleinopathies. 9 Our study suggests that ePD 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 lPD 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. For instance, AQP4 isoforms and endfeet anchoring, 37 , 38 , 39 the dynamic impact on glymphatic function, and αSyn transmission between neurons and astrocytes 40 all warrant future studies to reveal pathomechanisms for therapies.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique; (4) Funding resources.

L.W.: 1C, 3A

O.T.: 1C

F.S.: 1C

H.L.: 1C

J.L.: 1A, 2A

W.S.K.: 2C, 3B, 4

G.M.H.: 1A, 3A, 3B, 4

Y.H.F.: 1A, 1B, 1C, 2A, 2B, 3A, 4

Disclosures

Ethical Compliance Statement: The postmortem study was approved by the University of Sydney Human Research Ethics Committee (2019/491; 2019/589). We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The work is supported by funding from Defeat Multiple System Atrophy/Vaincre L'Atrophie Multisystématisée (Canada) and Defeat Multiple System Atrophy Australia (grant number: 2021–45), Defeat MSA Alliance (grant number: 2021–43), University of Sydney‐Fudan University BISA Flagship Research Program, and The Michael J. Fox Foundation for Parkinson's Research (MJFF17638). G.M.H. holds an NHMRC senior leadership fellowship (#1176607). The authors declare no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: G.M.H. has received research grant funding from the National Health and Medical Research Council of Australia (1191407, 2034292), Aligning Science Across Parkinson’s (ASAP‐000497, ASAP‐020505, ASAP‐020529, ASAP‐025184), Michael J Fox Foundation (MJFF‐021120, MJFF‐023703, MJFF‐024074), and National Institutes of Health USA (5RO1NS109209‐02, 1RO1NS123142‐01A1). Y.F. has received research grant funding from the Infectious Disease Society of America (ALZ‐ID‐0000000016).

Supporting information

Fig. S1. Polarization parameter correlations in controls (Ct), Parkinson's disease (PD), and multiple system atrophy (MSA).

Fig. S2. The impact of the biological factor on subregional AQP4 polarization and abundance.

Fig. S3. The AQP4 changes in staged Parkinson's disease (PD) and two phenotypes of multiple system atrophy (MSA) in white matter.

Fig. S4. AQP4 alteration analyses with neuritic plaque negative cases of control (Ct) and Parkinson's disease (PD).

Fig. S5. Pathological alpha‐synuclein (αSyn) load in the motor cortex of control (Ct) and multiple system atrophy (MSA) cases.

Table S1. Demographics of the postmortem cohort in neuropathological experiments.

MDS-40-2804-s001.docx (858.9KB, docx)

Acknowledgments

Postmortem tissues were supplied by the Sydney Brain Bank, supported by Neuroscience Research Australia and a special gift in memory of Jim Raftos from the Shaw family. The authors also acknowledge the facilities and the scientific and technical assistance of Microscopy Australia at the Australian Centre for Microscopy & Microanalysis at the University of Sydney. Open access publishing facilitated by The University of Sydney, as part of the Wiley ‐ The University of Sydney agreement via the Council of Australian University Librarians.

Contributor Information

Glenda M. Halliday, Email: glenda.halliday@sydney.edu.au.

YuHong Fu, Email: yuhong.fu@sydney.edu.au.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Fig. S1. Polarization parameter correlations in controls (Ct), Parkinson's disease (PD), and multiple system atrophy (MSA).

Fig. S2. The impact of the biological factor on subregional AQP4 polarization and abundance.

Fig. S3. The AQP4 changes in staged Parkinson's disease (PD) and two phenotypes of multiple system atrophy (MSA) in white matter.

Fig. S4. AQP4 alteration analyses with neuritic plaque negative cases of control (Ct) and Parkinson's disease (PD).

Fig. S5. Pathological alpha‐synuclein (αSyn) load in the motor cortex of control (Ct) and multiple system atrophy (MSA) cases.

Table S1. Demographics of the postmortem cohort in neuropathological experiments.

MDS-40-2804-s001.docx (858.9KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Articles from Movement Disorders are provided here courtesy of Wiley

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