PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts
BackgroundCurrent evidence suggests that microvessel disease is involved in Alzheimer’s disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevent...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1272361/full |
| _version_ | 1797390191800877056 |
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| author | Huaixing Wang Zongxiu Zhang Jarin Hongpaisan |
| author_facet | Huaixing Wang Zongxiu Zhang Jarin Hongpaisan |
| author_sort | Huaixing Wang |
| collection | DOAJ |
| description | BackgroundCurrent evidence suggests that microvessel disease is involved in Alzheimer’s disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs.MethodsTo induce brain microinfarcts, we injected triple transgenic (3×Tg) and wild-type (WT) control mice with microbeads (20 μm caliber) into common carotid arteries, with or without the DCPLA-ME (methyl-ester) for 2 weeks. After water maze training, mice at 16 months old were examined for confocal immunohistochemistry at a single cell or microvessel level in the hippocampal CA1 area, important for spatial memory storage, and in the dorsal hippocampus by western blots.ResultsIn 3×Tg mice without cerebral microinfarcts, an accelerating age-related increase in (mild) oxidative stress and hypoxia inducible factor (HIF)-1α, but a reduction in VEGF, mitochondrial transcription factor A (TFAM), and MnSOD were associated with capillary loss. The change was less pronounced in arterioles. However, in 3×Tg mice with cerebral microinfarcts, increasing arteriolar diameter and their wall cells were related with the strong oxidative DNA damage 8-hydroxy-2′-deoxyguanosine (8-OHdG), apoptosis (cleaved caspase 3), and sustained hypoxia (increased HIF-1α and VEGF/PKCε/extracellular signal regulated kinase or ERK pathway). Microocclusion enhanced the loss of the synaptic marker spinophilin, astrocytic number, and astrocyte-vascular coupling areas and demyelination of axons. DCPLA-ME prevented spatial memory defect; strong oxidative stress-related apoptosis; sustained hypoxia (by reducing HIF-1α and VEGF); and exaggerated cell repair in arteriolar walls, pericapillary space dilation, neuro-glial-vascular disruption, and demyelination.ConclusionIn conclusion, in 3×Tg mice with cerebral microinfarcts, sustained hypoxia (increased HIF-1α and VEGF signals) is dominant with arteriolar wall thickening, and DCPLA has a protective effect on sustained hypoxia. |
| first_indexed | 2024-03-08T23:07:09Z |
| format | Article |
| id | doaj.art-1cd77b74f1254c1bb6f100b98e17bd81 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-03-08T23:07:09Z |
| publishDate | 2023-12-01 |
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| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-1cd77b74f1254c1bb6f100b98e17bd812023-12-15T10:34:12ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652023-12-011510.3389/fnagi.2023.12723611272361PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarctsHuaixing WangZongxiu ZhangJarin HongpaisanBackgroundCurrent evidence suggests that microvessel disease is involved in Alzheimer’s disease (AD). Cerebrovascular disease correlates with cardiovascular disease and is complicated in ≈40% of AD patients. The protein kinase C (PKC) ε activator DCPLA can stimulate human antigen (Hu) R that prevents degradation and promotes the translation of mitochondrial Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF) mRNAs.MethodsTo induce brain microinfarcts, we injected triple transgenic (3×Tg) and wild-type (WT) control mice with microbeads (20 μm caliber) into common carotid arteries, with or without the DCPLA-ME (methyl-ester) for 2 weeks. After water maze training, mice at 16 months old were examined for confocal immunohistochemistry at a single cell or microvessel level in the hippocampal CA1 area, important for spatial memory storage, and in the dorsal hippocampus by western blots.ResultsIn 3×Tg mice without cerebral microinfarcts, an accelerating age-related increase in (mild) oxidative stress and hypoxia inducible factor (HIF)-1α, but a reduction in VEGF, mitochondrial transcription factor A (TFAM), and MnSOD were associated with capillary loss. The change was less pronounced in arterioles. However, in 3×Tg mice with cerebral microinfarcts, increasing arteriolar diameter and their wall cells were related with the strong oxidative DNA damage 8-hydroxy-2′-deoxyguanosine (8-OHdG), apoptosis (cleaved caspase 3), and sustained hypoxia (increased HIF-1α and VEGF/PKCε/extracellular signal regulated kinase or ERK pathway). Microocclusion enhanced the loss of the synaptic marker spinophilin, astrocytic number, and astrocyte-vascular coupling areas and demyelination of axons. DCPLA-ME prevented spatial memory defect; strong oxidative stress-related apoptosis; sustained hypoxia (by reducing HIF-1α and VEGF); and exaggerated cell repair in arteriolar walls, pericapillary space dilation, neuro-glial-vascular disruption, and demyelination.ConclusionIn conclusion, in 3×Tg mice with cerebral microinfarcts, sustained hypoxia (increased HIF-1α and VEGF signals) is dominant with arteriolar wall thickening, and DCPLA has a protective effect on sustained hypoxia.https://www.frontiersin.org/articles/10.3389/fnagi.2023.1272361/fullcerebrovascular diseasemicrovesselhypoxiaoxidative stressVEGF |
| spellingShingle | Huaixing Wang Zongxiu Zhang Jarin Hongpaisan PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts Frontiers in Aging Neuroscience cerebrovascular disease microvessel hypoxia oxidative stress VEGF |
| title | PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts |
| title_full | PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts |
| title_fullStr | PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts |
| title_full_unstemmed | PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts |
| title_short | PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer’s disease mice with cerebral microinfarcts |
| title_sort | pkcε activator protects hippocampal microvascular disruption and memory defect in 3 tg alzheimer s disease mice with cerebral microinfarcts |
| topic | cerebrovascular disease microvessel hypoxia oxidative stress VEGF |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2023.1272361/full |
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