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Curr Alzheimer Res. 2019;16(4):281-292. doi: 10.2174/1567205016666190228120254.

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

Author information

1
Department of Neurobiology, Sagol School of Neuroscience, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
2
Sackler School of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv, Israel.

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); MAPK; VEGF; adeno-associated virus; apolipoprotein E4 (apoE4); hippocampus; signaling; targeted replacement mice.

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