The role of MAPK’s signaling in mediating apoe4-driven pathology In Vivo

Shiran Salomon-Zimri, Amit Koren, Ariel Angel, Tali Ben-Zur, Daniel Offen, Daniel M. Michaelson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)281-292
Number of pages12
JournalCurrent Alzheimer Research
Volume16
Issue number4
DOIs
StatePublished - 2019

Keywords

  • Adeno-associated virus
  • Alzheimer’s disease (AD)
  • Apolipoprotein E4 (apoE4)
  • Hippocampus
  • MAPK
  • Signaling
  • Targeted replacement mice
  • VEGF

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