Abstract
Aims
Neuronal demise in Alzheimer’s disease (AD) occurs years later than the accumulation of amyloid-beta plaquesand neurofibrillary tangles, but the mechanisms underlying neuronal death remain unresolved. Increasingaccumulation of biometals (e.g. iron, zinc, copper, and manganese) increases oxidative stress, and theiraccumulation is worsened by cerebral amyloid angiopathy (CAA) which causes microbleeds with the depositionof iron. We hypothesized that AD studied in a mouse model with CAA (TgSwDI) causes pathological depositionof biometals with resulting dyshomeostasis.
Methods
Brains of TgSwDI mice, which deposit amyloid plaques and CAA from 3-6 months, and C57Bl/6j control mice,aged 7, 12, and 24 months (n=6-12 per age) were dissected into the cortex, hippocampus, thalamus, andcerebellum. The content of iron, zinc, copper, and manganese was measured using ICP-OES. The hippocampusand thalamus were also examined for gene expression of selected iron-handling proteins using TaqMan qPCR,and the hippocampi from 24 months mice were examined for their protein content using LC-MS/MS.
Results
The content of biometals varied among different brain regions, ages, and genotype. Combining the biometalcontent of each brain region revealed that TgSwDI mice had significantly different biometal profiles comparedto controls. The gene expression of ferritin light and heavy chains significantly decreased in TgSwDI mice at allages, while the expression of the transferrin receptor was unaffected. The LC-MS/MS analysis showed thatTgSwDI mice had severe gliosis without significant changes in iron-handling proteins.
Conclusions
Our findings show that the content of biometals is significantly changed in different brain regions of TgSwDImice with a simultaneous reduction in ferritin expression. The suppressed expression of ferritin isoformscombined with the change in biometal content likely contribute to oxidative stress and neuronal damage inTgSwDI mice.
Neuronal demise in Alzheimer’s disease (AD) occurs years later than the accumulation of amyloid-beta plaquesand neurofibrillary tangles, but the mechanisms underlying neuronal death remain unresolved. Increasingaccumulation of biometals (e.g. iron, zinc, copper, and manganese) increases oxidative stress, and theiraccumulation is worsened by cerebral amyloid angiopathy (CAA) which causes microbleeds with the depositionof iron. We hypothesized that AD studied in a mouse model with CAA (TgSwDI) causes pathological depositionof biometals with resulting dyshomeostasis.
Methods
Brains of TgSwDI mice, which deposit amyloid plaques and CAA from 3-6 months, and C57Bl/6j control mice,aged 7, 12, and 24 months (n=6-12 per age) were dissected into the cortex, hippocampus, thalamus, andcerebellum. The content of iron, zinc, copper, and manganese was measured using ICP-OES. The hippocampusand thalamus were also examined for gene expression of selected iron-handling proteins using TaqMan qPCR,and the hippocampi from 24 months mice were examined for their protein content using LC-MS/MS.
Results
The content of biometals varied among different brain regions, ages, and genotype. Combining the biometalcontent of each brain region revealed that TgSwDI mice had significantly different biometal profiles comparedto controls. The gene expression of ferritin light and heavy chains significantly decreased in TgSwDI mice at allages, while the expression of the transferrin receptor was unaffected. The LC-MS/MS analysis showed thatTgSwDI mice had severe gliosis without significant changes in iron-handling proteins.
Conclusions
Our findings show that the content of biometals is significantly changed in different brain regions of TgSwDImice with a simultaneous reduction in ferritin expression. The suppressed expression of ferritin isoformscombined with the change in biometal content likely contribute to oxidative stress and neuronal damage inTgSwDI mice.
| Original language | English |
|---|---|
| Publication date | 2023 |
| Publication status | Published - 2023 |
| Event | International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders - Gothenburg, Sweden Duration: 28 Mar 2023 → 1 Apr 2023 https://adpd.kenes.com/ |
Conference
| Conference | International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders |
|---|---|
| Country/Territory | Sweden |
| City | Gothenburg |
| Period | 28/03/2023 → 01/04/2023 |
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