Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease
Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have si...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-11-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996124002948 |
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| author | Michiko Sekiya Yasufumi Sakakibara Yu Hirota Naoki Ito Sachie Chikamatsu Kimi Takei Risa Nishijima Koichi M. Iijima |
| author_facet | Michiko Sekiya Yasufumi Sakakibara Yu Hirota Naoki Ito Sachie Chikamatsu Kimi Takei Risa Nishijima Koichi M. Iijima |
| author_sort | Michiko Sekiya |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of Aβ accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by Aβ pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (AppNLGF) mouse model of Aβ amyloidosis. The CE-TOFMS analysis of plasma samples from female wild-type (WT) and AppNLGF mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in AppNLGF mice, and altered metabolite profiles were enriched for nicotinate/nicotinamide metabolism. In AppNLGF mouse brains, NAD+ levels were unaltered, but mRNA levels of NAD+-synthesizing nicotinate phosphoribosyltransferase (Naprt) and NAD+-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding Aβ plaques in the cortex and hippocampus of female AppNLGF mouse brains, suggesting neuroinflammation increases NAD+ metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection. |
| format | Article |
| id | doaj-art-1e81ee9b26e9453894ae9f49ea970c43 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-1e81ee9b26e9453894ae9f49ea970c432024-11-20T05:06:28ZengElsevierNeurobiology of Disease1095-953X2024-11-01202106694Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's diseaseMichiko Sekiya0Yasufumi Sakakibara1Yu Hirota2Naoki Ito3Sachie Chikamatsu4Kimi Takei5Risa Nishijima6Koichi M. Iijima7Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; Corresponding authors at: Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDepartment of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Reseach Fellow of Japan Society for the Promotion of Science, Tokyo, JapanBrain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDepartment of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, JapanDepartment of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDepartment of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, JapanDepartment of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; Corresponding authors at: Department of Neurogenetics, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Amyloid-β (Aβ) accumulation triggers chronic neuroinflammation, initiating AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy underscore that blood-based biomarkers have significant advantages and applicability over conventional diagnostics and are an unmet clinical need. To further advance ongoing clinical trials and identify novel therapeutic targets for AD, developing additional plasma biomarkers closely associated with pathogenic mechanisms downstream of Aβ accumulation is critically important. To identify plasma metabolites reflective of neuroinflammation caused by Aβ pathology, we performed untargeted metabolomic analyses of the plasma by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) and analyzed the potential roles of the identified metabolic changes in the brain neuroinflammatory response using the female App knock-in (AppNLGF) mouse model of Aβ amyloidosis. The CE-TOFMS analysis of plasma samples from female wild-type (WT) and AppNLGF mice revealed that plasma levels of nicotinamide, a nicotinamide adenine dinucleotide (NAD+) precursor, were decreased in AppNLGF mice, and altered metabolite profiles were enriched for nicotinate/nicotinamide metabolism. In AppNLGF mouse brains, NAD+ levels were unaltered, but mRNA levels of NAD+-synthesizing nicotinate phosphoribosyltransferase (Naprt) and NAD+-degrading Cd38 genes were increased. These enzymes were induced in reactive astrocytes and microglia surrounding Aβ plaques in the cortex and hippocampus of female AppNLGF mouse brains, suggesting neuroinflammation increases NAD+ metabolism. This study suggests plasma nicotinamide could be indicative of the neuroinflammatory response and that nicotinate and nicotinamide metabolism are potential therapeutic targets for AD, by targeting both neuroinflammation and neuroprotection.http://www.sciencedirect.com/science/article/pii/S0969996124002948Alzheimer's disease (AD)Amyloid-β (Aβ)Metabolomic analysisApp knock-in mouseNicotinamideNAD+ |
| spellingShingle | Michiko Sekiya Yasufumi Sakakibara Yu Hirota Naoki Ito Sachie Chikamatsu Kimi Takei Risa Nishijima Koichi M. Iijima Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease Neurobiology of Disease Alzheimer's disease (AD) Amyloid-β (Aβ) Metabolomic analysis App knock-in mouse Nicotinamide NAD+ |
| title | Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease |
| title_full | Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease |
| title_fullStr | Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease |
| title_full_unstemmed | Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease |
| title_short | Decreased plasma nicotinamide and altered NAD+ metabolism in glial cells surrounding Aβ plaques in a mouse model of Alzheimer's disease |
| title_sort | decreased plasma nicotinamide and altered nad metabolism in glial cells surrounding aβ plaques in a mouse model of alzheimer s disease |
| topic | Alzheimer's disease (AD) Amyloid-β (Aβ) Metabolomic analysis App knock-in mouse Nicotinamide NAD+ |
| url | http://www.sciencedirect.com/science/article/pii/S0969996124002948 |
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