Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes
Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline. Uncovering the mechanisms of neurodegeneration in the early stages is essential to establish a treatment for AD. Recent research has proposed the hypothesis that amyloid-β (Aβ) oligomers elic...
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Nature Portfolio
2025-05-01
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| author | Kaito Nakata Joe Sakamoto Kohei Otomo Masanao Sato Hirokazu Ishii Motosuke Tsutsumi Ryosuke Enoki Tomomi Nemoto |
| author_facet | Kaito Nakata Joe Sakamoto Kohei Otomo Masanao Sato Hirokazu Ishii Motosuke Tsutsumi Ryosuke Enoki Tomomi Nemoto |
| author_sort | Kaito Nakata |
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| description | Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline. Uncovering the mechanisms of neurodegeneration in the early stages is essential to establish a treatment for AD. Recent research has proposed the hypothesis that amyloid-β (Aβ) oligomers elicit an excessive glutamate release from astrocytes toward synapses through intracellular free Ca2+ ([Ca2+] i ) elevations in astrocytes, finally resulting in neuronal dendritic spine loss. Under physiological conditions, astrocytic [Ca2+] i elevations range spatially from microdomains to network-wide propagation and temporally from milliseconds to tens of seconds. Astrocytic localized and fast [Ca2+] i elevations might correlate with glutamate release; however, the Aβ-induced alteration of localized, fast astrocytic [Ca2+] i elevations remains unexplored. In this study, we quantitatively investigated the Aβ dimers-induced changes in the spatial and temporal patterns of [Ca2+] i in a primary culture of astrocytes by two-photon excitation spinning-disk confocal microscopy. The frequency of fast [Ca2+] i elevations occurring locally in astrocytes (≤ 0.5 s, ≤ 35 µm2) and [Ca2+] i event occupancy relative to cell area significantly increased after exposure to Aβ dimers. The effect of Aβ dimers appeared above 500 nM, and these Aβ dimers-induced [Ca2+] i elevations were primarily mediated by a metabotropic purinergic receptor (P2Y1 receptor) and Ca2+ release from the endoplasmic reticulum. Our findings suggest that the Aβ dimers-induced alterations and hyperactivation of astrocytic [Ca2+] i is a candidate cellular mechanism in the early stages of AD. |
| format | Article |
| id | doaj-art-609e5d09a7d54b848f45e3e5d6a7d635 |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-609e5d09a7d54b848f45e3e5d6a7d6352025-08-20T03:22:07ZengNature PortfolioScientific Reports2045-23222025-05-0115111010.1038/s41598-025-03931-7Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytesKaito Nakata0Joe Sakamoto1Kohei Otomo2Masanao Sato3Hirokazu Ishii4Motosuke Tsutsumi5Ryosuke Enoki6Tomomi Nemoto7School of Life Science, The Graduate University for Advanced Studies, SOKENDAIDivision of Biophotonics, National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS)Division of Biophotonics, National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS)Laboratory of Applied Molecular Entomology, Division of Applied Bioscience, Research Faculty of Agriculture, Hokkaido UniversitySchool of Life Science, The Graduate University for Advanced Studies, SOKENDAIDivision of Biophotonics, National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences (NINS)School of Life Science, The Graduate University for Advanced Studies, SOKENDAISchool of Life Science, The Graduate University for Advanced Studies, SOKENDAIAbstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline. Uncovering the mechanisms of neurodegeneration in the early stages is essential to establish a treatment for AD. Recent research has proposed the hypothesis that amyloid-β (Aβ) oligomers elicit an excessive glutamate release from astrocytes toward synapses through intracellular free Ca2+ ([Ca2+] i ) elevations in astrocytes, finally resulting in neuronal dendritic spine loss. Under physiological conditions, astrocytic [Ca2+] i elevations range spatially from microdomains to network-wide propagation and temporally from milliseconds to tens of seconds. Astrocytic localized and fast [Ca2+] i elevations might correlate with glutamate release; however, the Aβ-induced alteration of localized, fast astrocytic [Ca2+] i elevations remains unexplored. In this study, we quantitatively investigated the Aβ dimers-induced changes in the spatial and temporal patterns of [Ca2+] i in a primary culture of astrocytes by two-photon excitation spinning-disk confocal microscopy. The frequency of fast [Ca2+] i elevations occurring locally in astrocytes (≤ 0.5 s, ≤ 35 µm2) and [Ca2+] i event occupancy relative to cell area significantly increased after exposure to Aβ dimers. The effect of Aβ dimers appeared above 500 nM, and these Aβ dimers-induced [Ca2+] i elevations were primarily mediated by a metabotropic purinergic receptor (P2Y1 receptor) and Ca2+ release from the endoplasmic reticulum. Our findings suggest that the Aβ dimers-induced alterations and hyperactivation of astrocytic [Ca2+] i is a candidate cellular mechanism in the early stages of AD.https://doi.org/10.1038/s41598-025-03931-7Amyloid-βAlzheimer’s diseaseAstrocyteCa2+Two-photon microscopy |
| spellingShingle | Kaito Nakata Joe Sakamoto Kohei Otomo Masanao Sato Hirokazu Ishii Motosuke Tsutsumi Ryosuke Enoki Tomomi Nemoto Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes Scientific Reports Amyloid-β Alzheimer’s disease Astrocyte Ca2+ Two-photon microscopy |
| title | Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes |
| title_full | Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes |
| title_fullStr | Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes |
| title_full_unstemmed | Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes |
| title_short | Amyloid-β-induced alteration of fast and localized calcium elevations in cultured astrocytes |
| title_sort | amyloid β induced alteration of fast and localized calcium elevations in cultured astrocytes |
| topic | Amyloid-β Alzheimer’s disease Astrocyte Ca2+ Two-photon microscopy |
| url | https://doi.org/10.1038/s41598-025-03931-7 |
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