GLP-1 receptor signaling restores aquaporin 4 subcellular polarization in reactive astrocytes and promotes amyloid β clearance in a mouse model of Alzheimer's disease.

Autor: Sasaki K; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan., Fujita H; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan. Electronic address: hirofuji@gipc.akita-u.ac.jp., Sato T; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan., Kato S; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan; Center for Medical Education and Training, Akita University Hospital, Akita, Japan., Takahashi Y; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan., Takeshita Y; Blood-Brain Barrier Research Center, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan., Kanda T; Department of Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan; Neuromuscular Center Yoshimizu Hospital, Shimonoseki, Yamaguchi, Japan., Saito T; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan; Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan., Saido TC; Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan., Hattori S; Division of Systems Medical Science, Center for Medical Science, Fujita Health University, Toyoake, Aichi, Japan; Research Creation Support Center, Aichi Medical University, Nagakute, Aichi, Japan., Hozumi Y; Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita, Japan., Yamada Y; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan; Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan; Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto, Japan. Electronic address: yamada.yuuichiro@a3.kepco.co.jp., Waki H; Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan. Electronic address: wakih@gipc.akita-u.ac.jp.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 Dec 31; Vol. 741, pp. 151016. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1016/j.bbrc.2024.151016
Abstrakt: The physiological actions of a gut hormone, glucagon-like peptide-1 (GLP-1), in Alzheimer's disease (AD) brain remain poorly understood, although GLP-1 receptor (GLP-1R) expression in this organ has been shown in several experimental studies. Therefore, we explored whether the GLP-1R signaling promotes the clearance of amyloid β (Aβ) (1-42) which is a core pathological hallmark of AD, focusing on the water channel protein aquaporin 4 (AQP4) localized to astrocyte endfeet perivascular membranes in intact brain. First, we confirmed that Glp1r mRNA is predominantly expressed at perivascular site of astrocytes in normal mouse cerebral cortex through in situ hybridization analysis. Next, we observed that 20-week subcutaneous administration of a GLP-1R agonist (GLP-1RA) liraglutide significantly reduced Aβ (1-42) accumulation in the cerebral cortex and improved spatial working memory in an AD mouse model, App NL-G-F/NL-G-F mice. Furthermore, our current data revealed that the 4-week liraglutide treatment relocalized subcellular AQP4 in morphologically injured reactive astrocytes of App NL-G-F/NL-G-F mice to the cell surface perivascular site through PKA-mediated AQP4 phosphorylation. Such translocation of phosphorylated AQP4 to astrocyte cell surface following incubation with liraglutide was observed also in the present in vitro study using the cell line in which AQP4 cDNA was introduced into immortalized human astrocyte. These results suggest that enhanced intracerebral GLP-1R signaling following peripheral administration of GLP-1RA restores AQP4 subcellular polarization in reactive astrocytes and would promote Aβ excretion possibly through increasing AQP4-mediated intracerebral water flux in the brain in AD.
Competing Interests: Declaration of competing interest K.S., H.F., S.K., Y.T., Y.Y., and H.W. received honoraria for lectures from Novo Nordisk. All other authors declared no competing interests.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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