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

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. 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.

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

“…The effects of the APOE genotype and HFD on apoE lipidation in the brain were assessed via blue native gel, and the results can be seen in Figure 5C, n = 3 lanes per group, where each lane represents a pull of three mice from the same group. In accordance with previous findings [70,72], under control diet conditions, apoE4 mice displayed hypolipidation of apoE relative to apoE3 mice. Importantly, the extent of lipidation of apoE in apoE3 and apoE4 mice was increased in mice exposed to the HFD, rendering the lipidation of apoE4 HFD mice similar to that of the apoE3 control diet mice.…”

“…The effects of the APOE genotype and HFD on apoE levels in the brain and plasma were assessed via immunoblots of hippocampal homogenates and plasma extracts from apoE3 and apoE4 control and HFD-fed mice. In accordance with previous findings [70], the total hippocampal apoE levels were significantly lower in apoE4 control diet mice relative to apoE3 control diet mice (0.55 ± 0.03 and 1 ± 0.03, respectively; *** p < 0.001). Interestingly, the HFD significantly decreased (*** p < 0.001) the levels of hippocampal apoE in apoE3 HFD mice relative to apoE3 control diet mice, rendering them closer to the levels of apoE4 control mice without affecting apoE4 mice ( Figure 5A).…”

“…In comparison, the present study observed an apoE4-dependent effect on insulin signaling at 6 months of age, as shown by measurements of the total and activated levels of IR and GSK-3β activation via Tyr216 and Ser9 phosphorylation. Seeing that the mice used in this study have a background of α-synuclein −/−, previously shown to exacerbate apoE4 pathology at a younger age [70], the observed effects on the insulin cascade may be due to this model's characteristic of a young age pathological phenotype. Another interesting variance in the results regards the effects of the HFD manipulation, where the present study found that the HFD impairs apoE3 mice, rendering them similar to apoE4 mice in various parameters; Zhao et al [48] observed no effect on apoE3 mice following the HFD.…”

“…The resulting mice were then crossbred to yield apoE4 and apoE3 homozygous mice on an α-syn−/− background. Accordingly, the present experiments were performed with apoE3 and apoE4 homozygous mice on an α-synuclein −/− background, in which we have previously shown that the apoE4 phenotype is more pronounced than in α-synuclein +/+ expressing mice [70]. These mice are referred to herein as apoE3 and apoE4 mice, respectively.…”

“…In the current study, we chose to focus on female mice, seeing that females are more susceptible to AD than males, and the interaction between gender and apoE4 has been demonstrated in numerous animal and human studies, resulting in the finding that apoE4-related pathology is more pronounced in females [18,69]. Furthermore, recent findings in our lab showed that apoE4-TR female mice have a more robust pathological phenotype than the corresponding male mice [70]. The results presented correspond to 2 female cohorts, consisting of 4 groups: 2 genotypes (apoE3 or apoE4) X 2 diets (control or HFD).…”