Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease
HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer’s disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of...
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MDPI AG
2024-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/2/189 |
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| author | Song-I Seol Dashdulam Davaanyam Sang-A Oh Eun-Hwa Lee Pyung-Lim Han Seung-Woo Kim Ja-Kyeong Lee |
| author_facet | Song-I Seol Dashdulam Davaanyam Sang-A Oh Eun-Hwa Lee Pyung-Lim Han Seung-Woo Kim Ja-Kyeong Lee |
| author_sort | Song-I Seol |
| collection | DOAJ |
| description | HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer’s disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in relation to the pathology of Alzheimer’s disease has not yet been studied in detail. Here, we investigated whether HMGB1 protein levels in brain tissue homogenates (frontal cortex and striatum) and sera from Tg-APP/PS1 mice, along with its cellular and subcellular localization in those regions, differed. Total HMGB1 levels were increased in the frontal cortices of aged wildtype (7.5 M) mice compared to young (3.5 M) mice, whereas total HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice (7.5 M) were significantly lower than those in age-matched wildtype mice. In contrast, total serum HMGB1 levels were enhanced in aged wildtype (7.5 M) mice and Tg-APP/PS1 mice (7.5 M). Further analysis indicated that nuclear HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice were significantly reduced compared to those in age-matched wildtype controls, and cytosolic HMGB1 levels were also significantly decreased. Triple-fluorescence immunohistochemical analysis indicated that HMGB1 appeared as a ring shape in the cytoplasm of most neurons and microglia in the frontal cortices of 9.5 M Tg-APP/PS1 mice, indicating that nuclear HMGB1 is reduced by aging and in Tg-APP/PS1 mice. Consistent with these observations, Aβ treatment of both primary cortical neuron and primary microglial cultures increased HMGB1 secretion in the media, in an Aβ-dose-dependent manner. Our results indicate that nuclear HMGB1 might be translocated from the nucleus to the cytoplasm in both neurons and microglia in the brains of Tg-APP/PS1 mice, and that it may subsequently be secreted extracellularly. |
| first_indexed | 2024-03-08T09:56:08Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T09:56:08Z |
| publishDate | 2024-01-01 |
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| spelling | doaj.art-bc9a75014e8e4762b37b7eb1006c0a822024-01-29T13:50:38ZengMDPI AGCells2073-44092024-01-0113218910.3390/cells13020189Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s DiseaseSong-I Seol0Dashdulam Davaanyam1Sang-A Oh2Eun-Hwa Lee3Pyung-Lim Han4Seung-Woo Kim5Ja-Kyeong Lee6Department of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of KoreaDepartment of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of KoreaDepartment of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of KoreaDepartment of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul 03760, Republic of KoreaDepartment of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul 03760, Republic of KoreaDepartment of Biomedical Sciences, Inha University School of Medicine, Inchon 22212, Republic of KoreaDepartment of Anatomy, Inha University School of Medicine, Incheon 22212, Republic of KoreaHMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer’s disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in relation to the pathology of Alzheimer’s disease has not yet been studied in detail. Here, we investigated whether HMGB1 protein levels in brain tissue homogenates (frontal cortex and striatum) and sera from Tg-APP/PS1 mice, along with its cellular and subcellular localization in those regions, differed. Total HMGB1 levels were increased in the frontal cortices of aged wildtype (7.5 M) mice compared to young (3.5 M) mice, whereas total HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice (7.5 M) were significantly lower than those in age-matched wildtype mice. In contrast, total serum HMGB1 levels were enhanced in aged wildtype (7.5 M) mice and Tg-APP/PS1 mice (7.5 M). Further analysis indicated that nuclear HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice were significantly reduced compared to those in age-matched wildtype controls, and cytosolic HMGB1 levels were also significantly decreased. Triple-fluorescence immunohistochemical analysis indicated that HMGB1 appeared as a ring shape in the cytoplasm of most neurons and microglia in the frontal cortices of 9.5 M Tg-APP/PS1 mice, indicating that nuclear HMGB1 is reduced by aging and in Tg-APP/PS1 mice. Consistent with these observations, Aβ treatment of both primary cortical neuron and primary microglial cultures increased HMGB1 secretion in the media, in an Aβ-dose-dependent manner. Our results indicate that nuclear HMGB1 might be translocated from the nucleus to the cytoplasm in both neurons and microglia in the brains of Tg-APP/PS1 mice, and that it may subsequently be secreted extracellularly.https://www.mdpi.com/2073-4409/13/2/189HMGB1ADAβfrontal cortexaging |
| spellingShingle | Song-I Seol Dashdulam Davaanyam Sang-A Oh Eun-Hwa Lee Pyung-Lim Han Seung-Woo Kim Ja-Kyeong Lee Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease Cells HMGB1 AD Aβ frontal cortex aging |
| title | Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease |
| title_full | Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease |
| title_fullStr | Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease |
| title_full_unstemmed | Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease |
| title_short | Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer’s Disease |
| title_sort | age dependent and aβ induced dynamic changes in the subcellular localization of hmgb1 in neurons and microglia in the brains of an animal model of alzheimer s disease |
| topic | HMGB1 AD Aβ frontal cortex aging |
| url | https://www.mdpi.com/2073-4409/13/2/189 |
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