ApoE4 Exacerbates Hippocampal Pathology Following Acute Brain Penetration Injury in Female Mice

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Abstract

The ɛ4 allele of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer’s disease. ApoE4 is also associated with poor recovery and functional outcome following traumatic brain injury. This study examined the effects of the apoE genotype on brain pathology following acute injury, induced by penetration of a needle through the cortex and hippocampus, at 3 and 14 days following the injury in female apoE3 and apoE4 α-synuclein-deficient targeted replacement (TR) mice. The results obtained revealed a marked inflammatory, synaptic and vascular response following the needle penetration injury (NPI). These results were found to be affected by the apoE genotype such that the inflammatory response, as measured utilizing the astrocytic marker GFAP and the microglial marker iba1, was faster and more prolonged in the apoE4 than in the apoE3 mice. The synaptic changes following the injury included a transient increase in synaptophysin levels in the apoE3 and not in the apoE4 mice, which was associated with a subsequent decrease in glutamatergic synapses, as measured utilizing VGluT1, in apoE4 and not in the apoE3 mice. Unlike these effects, measurements of the vasculature utilizing collagen IV as a marker revealed a significant increase which was similar in both apoE3 and apoE4 mice. Taken together, these results show that following acute brain injury, there is an apoE4-specific inflammatory and neuronal response to the injury. The NPI model provides a useful tool for studying the mechanism underlying the effects of apoE4 following acute brain injury and for the development of a corresponding anti-apoE4-targeted treatment.

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Acknowledgments

We thank Alex Smolar for his technical assistance.

Funding

This research was supported in part by grants from the Israel Science Foundation (grant no. 794/17), from the Sagol Foundation and from the Harold and Eleanore Foonberg Foundation.

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Correspondence to Daniel Michaelson.

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Ben-Moshe, H., Luz, I., Liraz, O. et al. ApoE4 Exacerbates Hippocampal Pathology Following Acute Brain Penetration Injury in Female Mice. J Mol Neurosci 70, 32–44 (2020). https://doi.org/10.1007/s12031-019-01397-7

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Keywords

  • Brain injury
  • apoE4
  • Inflammation
  • Neurodegeneration
  • Vascular