The Role of MAPK's Signaling in Mediating ApoE4-Driven Pathology In Vivo

Author(s): Shiran Salomon-Zimri, Amit Koren, Ariel Angel, Tali Ben-Zur, Daniel Offen, Daniel M. Michaelson*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 4 , 2019

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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.

Keywords: Alzheimer's disease (AD), apolipoprotein E4 (apoE4), VEGF, MAPK, signaling, adeno-associated virus, hippocampus, targeted replacement mice.

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Year: 2019
Page: [281 - 292]
Pages: 12
DOI: 10.2174/1567205016666190228120254
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