ApoE4 Exacerbates Hippocampal Pathology Following Acute Brain Penetration Injury in Female Mice
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.
KeywordsBrain injury apoE4 Inflammation Neurodegeneration Vascular
We thank Alex Smolar for his technical assistance.
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.
Compliance with Ethical Standards
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- Arendt T, Schindler C, Bruckner MK, Eschrich K, Bigl V, Zedlick D, Marcova L (1997) Plastic neuronal remodeling is impaired in patients with Alzheimer’s disease carrying apolipoprotein epsilon 4 allele. The Journal of neuroscience: the official journal of the Society for Neuroscience 17:516–529CrossRefGoogle Scholar
- Belinson H, Lev D, Masliah E, Michaelson DM (2008) Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. The Journal of neuroscience: the official journal of the Society for Neuroscience 28:4690–4701. https://doi.org/10.1523/JNEUROSCI.5633-07.2008 CrossRefGoogle Scholar
- Crawford F et al (2009) Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury. Neuroscience 159:1349–1362. https://doi.org/10.1016/j.neuroscience.2009.01.033 CrossRefGoogle Scholar
- de Bont N et al (1999) Apolipoprotein E knock-out mice are highly susceptible to endotoxemia and Klebsiella pneumoniae infection. J Lipid Res 40:680–685Google Scholar
- Dhungana H et al (2013) Western-type diet modulates inflammatory responses and impairs functional outcome following permanent middle cerebral artery occlusion in aged mice expressing the human apolipoprotein E4 allele. J Neuroinf 10:102. https://doi.org/10.1186/1742-2094-10-102 CrossRefGoogle Scholar
- Lin AL et al (2017) Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 37:217–226. https://doi.org/10.1177/0271678X15621575 CrossRefGoogle Scholar
- Maezawa I, Zaja-Milatovic S, Milatovic D, Stephen C, Sokal I, Maeda N, Montine TJ, Montine KS (2006b) Apolipoprotein E isoform-dependent dendritic recovery of hippocampal neurons following activation of innate immunity. J Neuroinflammation 3:21. https://doi.org/10.1186/1742-2094-3-21 CrossRefGoogle Scholar
- Mori T, Town T, Kobayashi M, Tan J, Fujita SC, Asano T (2004) Augmented delayed infarct expansion and reactive astrocytosis after permanent focal ischemia in apolipoprotein E4 knock-in mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 24:646–656. https://doi.org/10.1097/01.WCB.0000120787.53851.A4 CrossRefGoogle Scholar
- Mottahedin A, Ardalan M, Chumak T, Riebe I, Ek J, Mallard C (2017) Effect of neuroinflammation on synaptic organization and function in the developing brain: implications for neurodevelopmental and neurodegenerative disorders. Front Cell Neurosci 11:190. https://doi.org/10.3389/fncel.2017.00190 CrossRefGoogle Scholar
- Padgett CR, Summers MJ, Vickers JC, McCormack GH, Skilbeck CE (2016) Exploring the effect of the apolipoprotein E (APOE) gene on executive function, working memory, and processing speed during the early recovery period following traumatic brain injury. J Clin Exp Neuropsychol 38:551–560. https://doi.org/10.1080/13803395.2015.1137557 CrossRefGoogle Scholar
- Rohn TT, Day RJ, Sheffield CB, Rajic AJ, Poon WW (2014) Apolipoprotein E pathology in vascular dementia. Int J Clin Exp Pathol 7:938–947Google Scholar
- Roselaar SE, Daugherty A (1998) Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo. J Lipid Res 39:1740–1743Google Scholar
- Saffarpour S, Shaabani M, Naghdi N, Farahmandfar M, Janzadeh A, Nasirinezhad F (2017) In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain. Physiol Behav 175:97–103. https://doi.org/10.1016/j.physbeh.2017.03.025 CrossRefGoogle Scholar
- Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ, Hulette C, Crain B, Goldgaber D, Roses AD (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472CrossRefGoogle Scholar
- Sheng H et al (1998) Apolipoprotein E isoform-specific differences in outcome from focal ischemia in transgenic mice. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 18:361–366. https://doi.org/10.1097/00004647-199804000-00003 CrossRefGoogle Scholar
- Szekely CA, Breitner JC, Fitzpatrick AL, Rea TD, Psaty BM, Kuller LH, Zandi PP (2008) NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 70:17–24. https://doi.org/10.1212/01.wnl.0000284596.95156.48 CrossRefGoogle Scholar
- Van Dooren T et al (2006) Neuronal or glial expression of human apolipoprotein e4 affects parenchymal and vascular amyloid pathology differentially in different brain regions of double- and triple-transgenic mice. Am J Pathol 168:245–260. https://doi.org/10.2353/ajpath.2006.050752 CrossRefGoogle Scholar
- Yip AG, McKee AC, Green RC, Wells J, Young H, Cupples LA, Farrer LA (2005) APOE, vascular pathology, and the AD brain. Neurology 65:259–265. https://doi.org/10.1212/01.wnl.0000168863.49053.4d CrossRefGoogle Scholar