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

[ Vol. 16 , Issue. 4 ]

Author(s):

Shiran Salomon-Zimri, Amit Koren, Ariel Angel, Tali Ben-Zur, Daniel Offen and Daniel M. Michaelson*   Pages 281 - 292 ( 12 )

Abstract:


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.

Affiliation:

Department of Neurobiology, Sagol School of Neuroscience, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Department of Neurobiology, Sagol School of Neuroscience, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Sackler School of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Sackler School of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Sackler School of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Department of Neurobiology, Sagol School of Neuroscience, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv



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