| RRC ID |
87293
|
| 著者 |
Sasaki K, Fujita H, Sato T, Kato S, Takahashi Y, Takeshita Y, Kanda T, Saito T, Saido TC, Hattori S, Hozumi Y, Yamada Y, Waki H.
|
| タイトル |
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.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
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, AppNL-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 AppNL-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.
|
| 巻・号 |
741
|
| ページ |
151016
|
| 公開日 |
2024-12-31
|
| DOI |
10.1016/j.bbrc.2024.151016
|
| PII |
S0006-291X(24)01552-3
|
| PMID |
39577079
|
| MeSH |
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides* / metabolism
Animals
Aquaporin 4* / genetics
Aquaporin 4* / metabolism
Astrocytes* / drug effects
Astrocytes* / metabolism
Cell Polarity / drug effects
Cerebral Cortex / drug effects
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Disease Models, Animal*
Glucagon-Like Peptide-1 Receptor* / genetics
Glucagon-Like Peptide-1 Receptor* / metabolism
Humans
Liraglutide / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Peptide Fragments / metabolism
Signal Transduction*
|
| リソース情報 |
| 実験動物マウス |
RBRC06344 |
