PKCε activator protects hippocampal microvascular disruption and memory defect in 3×Tg-Alzheimer's disease mice with
Huaixing Wang1, Zongxiu Zhang1, Jarin Hongpaisan1
1Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States.
Insights
Microvessel disease contributes to Alzheimer's disease. DCPLA treatment protected against hypoxia and memory deficits in a mouse model, suggesting a therapeutic potential for cerebrovascular dysfunction.
Area of Science:
- Neuroscience
- Vascular Biology
- Biochemistry
Background:
- Microvessel disease is implicated in Alzheimer's disease (AD), affecting approximately 40% of patients.
- Cerebrovascular disease is closely linked to cardiovascular disease.
- Protein kinase C (PKC) ε activator DCPLA influences mRNA translation for Mn-superoxide dismutase (MnSOD) and vascular endothelial growth factor-A (VEGF).
Purpose of the Study:
- To investigate the role of DCPLA in a mouse model of Alzheimer's disease with induced cerebral microinfarcts.
- To evaluate the impact of DCPLA on oxidative stress, hypoxia, and cognitive function.
Main Methods:
- Triple transgenic (3×Tg) and wild-type (WT) mice were subjected to induced cerebral microinfarcts.
- Mice received DCPLA-methyl ester (DCPLA-ME) treatment.
- Cognitive function was assessed using the water maze test.
- Hippocampal tissues were analyzed using confocal immunohistochemistry and western blots.
Main Results:
- In 3×Tg mice, microinfarcts led to increased oxidative stress, apoptosis, sustained hypoxia (elevated HIF-1α and VEGF), and loss of synaptic markers.
- DCPLA-ME administration prevented spatial memory deficits.
- DCPLA-ME reduced markers of oxidative stress, apoptosis, and sustained hypoxia.
- DCPLA-ME mitigated arteriolar wall changes, neuro-glial-vascular disruption, and demyelination.
Conclusions:
- Sustained hypoxia and arteriolar wall thickening are key features in 3×Tg mice with cerebral microinfarcts.
- DCPLA demonstrates a protective effect against sustained hypoxia and associated pathologies.
- DCPLA shows potential as a therapeutic agent for cerebrovascular dysfunction in Alzheimer's disease.
Background:
Current 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.
Methods:
To 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.
Results:
In 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.
Conclusion:
In 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.
