Advertisement

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

  • Hila Ben-Moshe
  • Ishai Luz
  • Ori Liraz
  • Anat Boehm-Cagan
  • Shiran Salomon-Zimri
  • Daniel MichaelsonEmail author
Article

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.

Keywords

Brain injury apoE4 Inflammation Neurodegeneration Vascular 

Notes

Acknowledgments

We thank Alex Smolar for his technical assistance.

Funding Information

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

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 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
  2. Arvanitakis Z, Leurgans SE, Wang Z, Wilson RS, Bennett DA, Schneider JA (2011) Cerebral amyloid angiopathy pathology and cognitive domains in older persons. Ann Neurol 69:320–327.  https://doi.org/10.1002/ana.22112 CrossRefGoogle Scholar
  3. Azad NA, Al Bugami M, Loy-English I (2007) Gender differences in dementia risk factors. Gender Med 4:120–129CrossRefGoogle Scholar
  4. Bar R, Boehm-Cagan A, Luz I, Kleper-Wall Y, Michaelson DM (2018) The effects of apolipoprotein E genotype, alpha-synuclein deficiency, and sex on brain synaptic and Alzheimer’s disease-related pathology. Alzheimer’s Dement 10:1–11.  https://doi.org/10.1016/j.dadm.2017.08.003 Google Scholar
  5. Belinson H, Michaelson DM (2009) ApoE4-dependent Abeta-mediated neurodegeneration is associated with inflammatory activation in the hippocampus but not the septum. J Neural Transm 116:1427–1434.  https://doi.org/10.1007/s00702-009-0218-9 CrossRefGoogle Scholar
  6. 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
  7. Burns MP, Noble WJ, Olm V, Gaynor K, Casey E, LaFrancois J, Wang L, Duff K (2003) Co-localization of cholesterol, apolipoprotein E and fibrillar Abeta in amyloid plaques brain research. Mol Brain Res 110:119–125CrossRefGoogle Scholar
  8. Busche MA, Konnerth A (2016) Impairments of neural circuit function in Alzheimer’s disease philosophical transactions of the Royal Society of London Series B. Biol Sci 371:20150429.  https://doi.org/10.1098/rstb.2015.0429 CrossRefGoogle Scholar
  9. Cook M, Baker N, Lanes S, Bullock R, Wentworth C, Arrighi HM (2015) Incidence of stroke and seizure in Alzheimer’s disease dementia. Age Ageing 44:695–699.  https://doi.org/10.1093/ageing/afv061 CrossRefGoogle Scholar
  10. Corder EH et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923CrossRefGoogle Scholar
  11. 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
  12. 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
  13. 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
  14. Egensperger R, Kosel S, von Eitzen U, Graeber MB (1998) Microglial activation in Alzheimer disease: association with APOE genotype. Brain Pathol 8:439–447CrossRefGoogle Scholar
  15. Funakubo Asanuma Y (2012) Accelerated atherosclerosis and inflammation in systemic lupus erythematosus. Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 35:470–480CrossRefGoogle Scholar
  16. Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT (1995) Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol 38:254–259.  https://doi.org/10.1002/ana.410380219 CrossRefGoogle Scholar
  17. Grinberg LT, Thal DR (2010) Vascular pathology in the aged human brain. Acta Neuropathol 119:277–290.  https://doi.org/10.1007/s00401-010-0652-7 CrossRefGoogle Scholar
  18. Haas A, Liraz O, Michaelson DM (2012) The effects of apolipoproteins E3 and E4 on the transforming growth factor-beta system in targeted replacement mice. Neurodegener Dis 10:41–45.  https://doi.org/10.1159/000334902 CrossRefGoogle Scholar
  19. Hartig W, Bruckner G, Schmidt C, Brauer K, Bodewitz G, Turner JD, Bigl V (1997) Co-localization of beta-amyloid peptides, apolipoprotein E and glial markers in senile plaques in the prefrontal cortex of old rhesus monkeys. Brain Res 751:315–322CrossRefGoogle Scholar
  20. Hartman RE, Laurer H, Longhi L, Bales KR, Paul SM, McIntosh TK, Holtzman DM (2002) Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer’s disease. J Neurosci 22:10083–10087CrossRefGoogle Scholar
  21. James ML, Sullivan PM, Lascola CD, Vitek MP, Laskowitz DT (2009) Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage. Stroke 40:632–639.  https://doi.org/10.1161/STROKEAHA.108.530402 CrossRefGoogle Scholar
  22. Ji Y, Gong Y, Gan W, Beach T, Holtzman DM, Wisniewski T (2003) Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer’s disease patients. Neuroscience 122:305–315CrossRefGoogle Scholar
  23. Jofre-Monseny L et al (2007) Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression. Biochem Biophys Res Commun 357:319–324.  https://doi.org/10.1016/j.bbrc.2007.03.150 CrossRefGoogle Scholar
  24. Jofre-Monseny L, Minihane AM, Rimbach G (2008) Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol Nutr Food Res 52:131–145.  https://doi.org/10.1002/mnfr.200700322 CrossRefGoogle Scholar
  25. Kim SK, Nabekura J, Koizumi S (2017) Astrocyte-mediated synapse remodeling in the pathological brain. Glia 65:1719–1727.  https://doi.org/10.1002/glia.23169 CrossRefGoogle Scholar
  26. Laskowitz DT, Goel S, Bennett ER, Matthew WD (1997) Apolipoprotein E suppresses glial cell secretion of TNF alpha. J Neuroimmunol 76:70–74CrossRefGoogle Scholar
  27. Laskowitz DT, Song P, Wang H, Mace B, Sullivan PM, Vitek MP, Dawson HN (2010) Traumatic brain injury exacerbates neurodegenerative pathology: improvement with an apolipoprotein E-based therapeutic. J Neurotrauma 27:1983–1995.  https://doi.org/10.1089/neu.2010.1396 CrossRefGoogle Scholar
  28. Levi O, Jongen-Relo AL, Feldon J, Roses AD, Michaelson DM (2003) ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol Dis 13:273–282CrossRefGoogle Scholar
  29. 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
  30. Liraz O, Boehm-Cagan A, Michaelson DM (2013) ApoE4 induces Abeta42, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice. Mol Neurodegen 8:16.  https://doi.org/10.1186/1750-1326-8-16 CrossRefGoogle Scholar
  31. Liu L, Fujimoto M, Kawakita F, Nakano F, Imanaka-Yoshida K, Yoshida T, Suzuki H (2016) Anti-vascular endothelial growth factor treatment suppresses early brain injury after subarachnoid hemorrhage in mice. Mol Neurobiol 53:4529–4538.  https://doi.org/10.1007/s12035-015-9386-9 CrossRefGoogle Scholar
  32. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241.  https://doi.org/10.1038/35025203 CrossRefGoogle Scholar
  33. Lynch JR, Morgan D, Mance J, Matthew WD, Laskowitz DT (2001) Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response. J Neuroimmunol 114:107–113CrossRefGoogle Scholar
  34. Maezawa I, Nivison M, Montine KS, Maeda N, Montine TJ (2006a) Neurotoxicity from innate immune response is greatest with targeted replacement of E4 allele of apolipoprotein E gene and is mediated by microglial p38MAPK. Faseb J 20:797–799CrossRefGoogle Scholar
  35. 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
  36. Mahley RW, Huang Y (2012) Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron 76:871–885.  https://doi.org/10.1016/j.neuron.2012.11.020 CrossRefGoogle Scholar
  37. 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
  38. 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
  39. Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M (2011) Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem 286:17536–17542CrossRefGoogle Scholar
  40. Ophir G, Amariglio N, Jacob-Hirsch J, Elkon R, Rechavi G, Michaelson DM (2005) Apolipoprotein E4 enhances brain inflammation by modulation of the NF-kappaB signaling cascade. Neurobiol Dis 20:709–718CrossRefGoogle Scholar
  41. 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
  42. Purushothuman S, Marotte L, Stowe S, Johnstone DM, Stone J (2013) The response of cerebral cortex to haemorrhagic damage: experimental evidence from a penetrating injury model. PloS one 8:e59740.  https://doi.org/10.1371/journal.pone.0059740 CrossRefGoogle Scholar
  43. Rodriguez GA, Tai LM, LaDu MJ, Rebeck GW (2014) Human APOE4 increases microglia reactivity at Abeta plaques in a mouse model of Abeta deposition. J Neuroinflamm 11:111.  https://doi.org/10.1186/1742-2094-11-111 CrossRefGoogle Scholar
  44. 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
  45. 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
  46. Roses AD (1996) Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med 47:387–400.  https://doi.org/10.1146/annurev.med.47.1.387 CrossRefGoogle Scholar
  47. Roses AD (1997) Apolipoprotein E, a gene with complex biological interactions in the aging brain. Neurobiol Dis 4:170–185.  https://doi.org/10.1006/nbdi.1997.0161 CrossRefGoogle Scholar
  48. Sabo T et al (2000) Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: the allele E3 is neuroprotective whereas E4 increases fatalities. Neuroscience 101:879–884CrossRefGoogle Scholar
  49. 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
  50. Sandhir R, Onyszchuk G, Berman NE (2008) Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Exp Neurol 213:372–380.  https://doi.org/10.1016/j.expneurol.2008.06.013 CrossRefGoogle Scholar
  51. 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
  52. Schmechel DE et al (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90:9649–9653CrossRefGoogle Scholar
  53. 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
  54. Shi Y et al (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–527.  https://doi.org/10.1038/nature24016 CrossRefGoogle Scholar
  55. Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78:539–552.  https://doi.org/10.1016/j.bcp.2009.04.029 CrossRefGoogle Scholar
  56. Strittmatter WJ, Roses AD (1996) Apolipoprotein E and Alzheimer’s disease. Annu Rev Neurosci 19:53–77CrossRefGoogle Scholar
  57. Sullivan PM et al (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272:17972–17980CrossRefGoogle Scholar
  58. Sweeney SE, Firestein GS (2004) Rheumatoid arthritis: regulation of synovial inflammation. Int J Biochem Cell Biol 36:372–378CrossRefGoogle Scholar
  59. 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
  60. Tedgui A, Mallat Z (2001) Anti-inflammatory mechanisms in the vascular wall. Circ Res 88:877–887CrossRefGoogle Scholar
  61. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580CrossRefGoogle Scholar
  62. Teter B (2004) ApoE-dependent plasticity in Alzheimer’s disease. J Mol Neurosci: MN 23:167–179.  https://doi.org/10.1385/JMN:23:3:167 CrossRefGoogle Scholar
  63. Ungar L, Altmann A, Greicius MD (2014) Apolipoprotein E, gender, and Alzheimer’s disease: an overlooked, but potent and promising interaction. Brain Imaging Behav 8:262–273.  https://doi.org/10.1007/s11682-013-9272-x CrossRefGoogle Scholar
  64. 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
  65. Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252.  https://doi.org/10.1016/S1474-4422(10)70325-2 CrossRefGoogle Scholar
  66. Viswanathan A, Greenberg SM (2011) Cerebral amyloid angiopathy in the elderly. Ann Neurol 70:871–880.  https://doi.org/10.1002/ana.22516 CrossRefGoogle Scholar
  67. Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr (1991) Cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 30:637–649.  https://doi.org/10.1002/ana.410300503 CrossRefGoogle Scholar
  68. 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
  69. Zhang HH et al (2012a) Increased synaptophysin is involved in inflammation-induced heat hyperalgesia mediated by cyclin-dependent kinase 5 in rats. PloS one 7:e46666.  https://doi.org/10.1371/journal.pone.0046666 CrossRefGoogle Scholar
  70. Zhang XM et al (2012b) Overexpression of apolipoprotein E4 increases kainic-acid-induced hippocampal neurodegeneration. Exp Neurol 233:323–332.  https://doi.org/10.1016/j.expneurol.2011.10.024 CrossRefGoogle Scholar
  71. Zhu Y, Nwabuisi-Heath E, Dumanis SB, Tai LM, Yu C, Rebeck GW, Ladu MJ (2012) APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 60:559–569CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of NeuroscienceTel Aviv UniversityTel AvivIsrael

Personalised recommendations