Regional differences in astrocytic Aquaporin-4 protein levels and distribution in aging and Alzheimer's disease in down syndrome

Cherie A Stringer¹, Haley K S Miyasato², Kevin A Camey³, Krina A Ghadia⁴, Elizabeth J Andrews⁵, Phong T Ngo⁶, Jesse R Pascual⁷, Sierra T Wright⁸, Justine A Silva⁹, Brianna M Gawronski¹⁰, Lourdes Gonzalez¹¹, Kevin A Wood¹², Michael J Phelan¹³, Florence Lai¹⁴, Frederick A Schmitt¹⁵, Jordan P Harp¹⁶, Adam M Brickman¹⁷, Patrick J Lao¹⁸, Mark E Mapstone¹⁹, Julia K Kofler²⁰, Milos D Ikonomovic²¹, Elizabeth Head²²; Alzheimer Biomarkers Consortium - Down Syndrome (ABC-DS)

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: clepe1@uci.edu.
² Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: Haley.miyasato@wsu.edu.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: camey@usc.edu.
⁴ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: kghadia@uci.edu.
⁵ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: ejandrews@uci.edu.
⁶ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA.
⁷ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: jesserp@uci.edu.
⁸ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA; Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA. Electronic address: stwright@uci.edu.
⁹ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA; Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Center for Aging Research in Down Syndrome, University of California, Irvine, CA, USA. Electronic address: justias3@uci.edu.
¹⁰ Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA. Electronic address: bgawrons@uci.edu.
¹¹ Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA. Electronic address: lourdeg3@uci.edu.
¹² Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA. Electronic address: woodka@uci.edu.
¹³ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: phelanm@uci.edu.
¹⁴ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: flai@partners.org.
¹⁵ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: fascom@uky.edu.
¹⁶ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: jordanharp@uky.edu.
¹⁷ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and the Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: amb2139@cumc.columbia.edu.
¹⁸ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and the Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: pjl2133@cumc.columbia.edu.
¹⁹ Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Department of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: mark.mapstone@uci.edu.
²⁰ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; University of Kentucky Department of Neurology, Lexington, KY, USA. Electronic address: koflerjk@upmc.edu.
²¹ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Department of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: ikonomovimd@upmc.edu.
²² Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA; Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Center for Aging Research in Down Syndrome, University of California, Irvine, CA, USA. Electronic address: heade@uci.edu.

PMID: 40987419
DOI: 10.1016/j.nbd.2025.107114

Regional differences in astrocytic Aquaporin-4 protein levels and distribution in aging and Alzheimer's disease in down syndrome

Cherie A Stringer et al. Neurobiol Dis. 2025.

. 2025 Sep 21:216:107114.

doi: 10.1016/j.nbd.2025.107114. Online ahead of print.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: clepe1@uci.edu.
² Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: Haley.miyasato@wsu.edu.
³ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: camey@usc.edu.
⁴ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: kghadia@uci.edu.
⁵ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: ejandrews@uci.edu.
⁶ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA.
⁷ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: jesserp@uci.edu.
⁸ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA; Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA. Electronic address: stwright@uci.edu.
⁹ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA; Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Center for Aging Research in Down Syndrome, University of California, Irvine, CA, USA. Electronic address: justias3@uci.edu.
¹⁰ Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA. Electronic address: bgawrons@uci.edu.
¹¹ Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA. Electronic address: lourdeg3@uci.edu.
¹² Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA. Electronic address: woodka@uci.edu.
¹³ Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA. Electronic address: phelanm@uci.edu.
¹⁴ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: flai@partners.org.
¹⁵ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: fascom@uky.edu.
¹⁶ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: jordanharp@uky.edu.
¹⁷ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and the Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: amb2139@cumc.columbia.edu.
¹⁸ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and the Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Electronic address: pjl2133@cumc.columbia.edu.
¹⁹ Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Department of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: mark.mapstone@uci.edu.
²⁰ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; University of Kentucky Department of Neurology, Lexington, KY, USA. Electronic address: koflerjk@upmc.edu.
²¹ Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Department of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA. Electronic address: ikonomovimd@upmc.edu.
²² Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA; Alzheimer's Disease Research Center, University of California, Irvine, CA, USA; University of California, Irvine Institute for Memory Impairments and Neurological Disorders, CA, USA; Alzheimer Biomarker Consortium-Down Syndrome, University of California, Irvine, CA, USA; Center for Aging Research in Down Syndrome, University of California, Irvine, CA, USA. Electronic address: heade@uci.edu.

PMID: 40987419
DOI: 10.1016/j.nbd.2025.107114

Abstract

Aquaporin-4 (AQP4) is implicated in Alzheimer's disease (AD) pathology through its role in astrocytic function, cerebrovascular integrity, and beta-amyloid (Aβ) clearance. Impaired Aβ clearance in AD is linked to changes in AQP4 distribution; however, the role of AQP4 in AD associated with Down Syndrome (DS) is poorly understood. This study investigates AQP4 protein levels, its relationship with Aβ deposition, and distribution patterns in DS. Using human post-mortem brain sections from the frontal and occipital cortex, we analyzed AQP4 and Aβ levels in samples from neurotypical controls, DS, DS with AD (DSAD), and late onset AD (LOAD). Protein levels and distribution were assessed using immunohistochemistry and immunofluorescence with quantitative imaging tools. AQP4 protein levels were higher with age in both neurotypical control and DS groups, but not in the LOAD group. AQP4 and Aβ were positively correlated with age in the frontal cortex of all groups. AQP4 and Aβ were positively correlated with each other after adjusting for age in the frontal cortex in both the control and DS groups which was not observed in the occipital cortex. In the frontal cortex of both DS and DSAD, AQP4 was more frequently distributed to the soma and proximal branches and less to astrocytic endfeet compared to the control group, consistent with previous reports of impaired glymphatic clearance and perivascular regulation. These findings support a relationship between altered AQP4 protein levels and distribution, Aβ accumulation, and region-specific vulnerability in DS and AD.

Keywords: Aging; Astrocytes; Glia; Neurodegeneration; Trisomy 21; beta-amyloid.

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Declaration of competing interest The authors report no conflicts of interest.

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Regional differences in astrocytic Aquaporin-4 protein levels and distribution in aging and Alzheimer's disease in down syndrome

Affiliations

Regional differences in astrocytic Aquaporin-4 protein levels and distribution in aging and Alzheimer's disease in down syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources