Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease
Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a clas...
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000142 |
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| author | Wenxuan Wang Sarah J. Myers Nikita Ollen-Bittle Shawn N. Whitehead |
| author_facet | Wenxuan Wang Sarah J. Myers Nikita Ollen-Bittle Shawn N. Whitehead |
| author_sort | Wenxuan Wang |
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| description | Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD. |
| format | Article |
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| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj-art-d8edc78929f848ffa27554a53b8f5fd32025-01-24T04:44:43ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106798Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's diseaseWenxuan Wang0Sarah J. Myers1Nikita Ollen-Bittle2Shawn N. Whitehead3Vulnerable Brain Lab, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, CanadaVulnerable Brain Lab, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, CanadaVulnerable Brain Lab, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, CanadaCorresponding author at: Department of Anatomy and Cell Biology, 458 Medical Sciences Building, The University of Western Ontario, London, Ontario N6A 3K7, Canada.; Vulnerable Brain Lab, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 5C1, CanadaAlzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.http://www.sciencedirect.com/science/article/pii/S0969996125000142Alzheimer's diseaseAgingAmyloidGangliosideLipid dysregulationMass spectrometry imaging |
| spellingShingle | Wenxuan Wang Sarah J. Myers Nikita Ollen-Bittle Shawn N. Whitehead Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease Neurobiology of Disease Alzheimer's disease Aging Amyloid Ganglioside Lipid dysregulation Mass spectrometry imaging |
| title | Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease |
| title_full | Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease |
| title_fullStr | Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease |
| title_full_unstemmed | Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease |
| title_short | Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease |
| title_sort | elevation of ganglioside degradation pathway drives gm2 and gm3 within amyloid plaques in a transgenic mouse model of alzheimer s disease |
| topic | Alzheimer's disease Aging Amyloid Ganglioside Lipid dysregulation Mass spectrometry imaging |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000142 |
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