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The Role of MAPK's Signaling in Mediating ApoE4-Driven Pathology In Vivo
Shiran Salomon-Zimri1, Amit Koren1, Ariel Angel2
1Department of Neurobiology, Sagol School of Neuroscience, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Background:
Alzheimer's Disease (AD) is associated with impairments in key brain Mitogen- Activated Protein Kinase (MAPK) signaling cascades including the p38, c-Jun N-terminal kinase (JNK), ERK and Akt pathways. Apolipoprotein E4 (ApoE4) is the most prevalent genetic risk factor of AD.
Objectives:
To investigate the extent to which the MAPK signaling pathway plays a role in mediating the pathological effects of apoE4 and can be reversed by experimental manipulations.
Methods:
Measurements of total level and activation of MAPK signaling pathway factors, obtained utilizing immunoblot assay of hippocampal tissues from naïve and viral-treated apoE3 and apoE4 targeted replacement mice.
Results:
ApoE4 mice showed robust activation of the stress related p38 and JNK pathways and a corresponding decrease in Akt activity, which is coupled to activation of GSK3β and tau hyperphosphorylation. There was no effect on the ERK pathway. We have previously shown that the apoE4- related pathology, namely; accumulation of Aβ, hyper-phosphorylated tau, synaptic impairments and decreased VEGF levels can be reversed by up-regulation of VEGF level utilizing a VEGF-expressing adeno-associated virus. Utilizing this approach, we assessed the extent to which the AD-hallmark and synaptic pathologies of apoE4 are related to the corresponding MAPK signaling effects. This revealed that the reversal of the apoE4-driven pathology via VEGF treatment was associated with a reversal of the p38 and Akt related effects.
Conclusion:
Taken together, these results suggest that the p38 and Akt pathways play a role in mediating the AD-related pathological effects of apoE4 in the hippocampus.
Insights
Alzheimer's disease (AD) involves impaired MAPK signaling. ApoE4, a major AD risk factor, activates p38/JNK and inhibits Akt, contributing to AD pathology. VEGF therapy reversed these effects.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's Disease (AD) is linked to impaired Mitogen-Activated Protein Kinase (MAPK) signaling pathways.
- Apolipoprotein E4 (ApoE4) is the primary genetic risk factor for AD.
Purpose of the Study:
- To determine the role of MAPK signaling in mediating ApoE4's pathological effects in AD.
- To investigate if these effects can be reversed through experimental manipulation.
Main Methods:
- Utilized immunoblot assays on hippocampal tissues from ApoE3 and ApoE4 targeted replacement mice.
- Measured total levels and activation states of key MAPK pathway factors.
Main Results:
- ApoE4 mice exhibited increased p38 and JNK pathway activation and decreased Akt activity, leading to GSK3β activation and tau hyperphosphorylation.
- Vascular Endothelial Growth Factor (VEGF) therapy reversed ApoE4-associated pathologies, including Aβ accumulation, tau hyperphosphorylation, and synaptic deficits.
- VEGF treatment also reversed the observed alterations in p38 and Akt pathway activity.
Conclusions:
- The p38 and Akt signaling pathways are implicated in mediating the AD-related pathological effects driven by ApoE4 in the hippocampus.