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Involvement of Apoptosis-Inducing Factor (AIF) in Neuronal Cell Death Following Cerebral Ischemia

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Acute Neuronal Injury

Abstract

Delayed neuronal death is a hallmark of infarct development and sustained functional impairment in rodent models of focal cerebral ischemia, an experimental paradigm resembling ischemic stroke in humans. The exact molecular pathophysiology of this still enigmatic event is not only of academic interest but may hold the key for novel therapeutic strategies for human stroke. There is general understanding that acute lack of perfusion leads to rapid necrotic-oncotic cell death in the core of the ischemic infarct. In contrast, conditions associated with severely reduced, but not immediately lethal reductions of cerebral blood flow in the ischemic penumbra likely result in delayed and more programmed type of neuronal cell death. Based on results first obtained from non-neuronal cells, cysteine aspartate proteases (caspases) were described as key modulators of this process. More recently, however, it became clear that also caspase-independent mechanisms play a significant role for ischemia-induced delayed neuronal cell loss. In this chapter, we review the role of one of the first described caspase-independent cell death proteins, apoptosis-inducing factor (AIF), for post-ischemic brain damage. Our conclusion is that there is compelling evidence for a causal role of AIF in neuronal cell death following experimental stroke and other neurological disorders associated with cerebral ischemia. Hence, AIF and other, more recently described subtypes of caspase-independent cell death may provide promising targets for therapeutic interventions in cerebrovascular disease.

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References

  • Adams HP Jr, del ZG, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF (2007) Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 115:e478–e534

    Article  PubMed  Google Scholar 

  • Andrabi SA, Kang HC, Haince JF, Lee YI, Zhang J, Chi Z, West AB, Koehler RC, Poirier GG, Dawson TM, Dawson VL (2011) Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nat Med 17:692–699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Artus C, Boujrad H, Bouharrour A, Brunelle MN, Hoos S, Yuste VJ, Lenormand P, Rousselle JC, Namane A, England P, Lorenzo HK, Susin SA (2010) AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX. EMBO J 29:1585–1599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Astrup J, Siesjo BK, Symon L (1981) Thresholds in cerebral ischemia—the ischemic penumbra. Stroke 12:723–725

    Article  CAS  PubMed  Google Scholar 

  • Baritaud M, Boujrad H, Lorenzo HK, Krantic S, Susin SA (2010) Histone H2AX: the missing link in AIF-mediated caspase-independent programmed necrosis. Cell Cycle 9:3166–3173

    Article  CAS  PubMed  Google Scholar 

  • Becattini B, Culmsee C, Leone M, Zhai D, Zhang X, Crowell KJ, Rega MF, Landshamer S, Reed JC, Plesnila N, Pellecchia M (2006) Structure-activity relationships by interligand NOE-based design and synthesis of antiapoptotic compounds targeting Bid. Proc Natl Acad Sci U S A 103:12602–12606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao G, Pei W, Lan J, Stetler RA, Luo Y, Nagayama T, Graham SH, Yin XM, Simon RP, Chen J (2001) Caspase-activated DNase/DNA fragmentation factor 40 mediates apoptotic DNA fragmentation in transient cerebral ischemia and in neuronal cultures. J Neurosci 21:4678–4690

    Article  CAS  PubMed  Google Scholar 

  • Cao G, Pei W, Ge H, Liang Q, Luo Y, Sharp FR, Lu A, Ran R, Graham SH, Chen J (2002) In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J Neurosci 22:5423–5431

    Article  CAS  PubMed  Google Scholar 

  • Cao G, Clark RS, Pei W, Yin W, Zhang F, Sun FY, Graham SH, Chen J (2003) Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab 23:1137–1150

    Article  CAS  PubMed  Google Scholar 

  • Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben Ari Y (1996) Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–194

    Article  CAS  PubMed  Google Scholar 

  • Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, Slack RS (2002) Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 158:507–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellecchia M, Blomgren K, Plesnila N (2005) Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 25:10262–10272

    Article  CAS  PubMed  Google Scholar 

  • Daugas E, Nochy D, Ravagnan L, Loeffler M, Susin SA, Zamzami N, Kroemer G (2000) Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. FEBS Lett 476:118–123

    Article  CAS  PubMed  Google Scholar 

  • D’Orsi B, Kilbride SM, Chen G, Perez AS, Bonner HP, Pfeiffer S, Plesnila N, Engel T, Henshall DC, Dussmann H, Prehn JH (2015) Bax regulates neuronal Ca2+ homeostasis. J Neurosci 35:1706–1722

    Article  CAS  PubMed  Google Scholar 

  • Doti N, Reuther C, Scognamiglio PL, Dolga AM, Plesnila N, Ruvo M, Culmsee C (2014) Inhibition of the AIF/CypA complex protects against intrinsic death pathways induced by oxidative stress. Cell Death Dis 5:e993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du C, Hu R, Csernansky CA, Hsu CY, Choi DW (1996) Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 16:195–201

    Article  CAS  PubMed  Google Scholar 

  • Endres M, Namura S, Shimizu-Sasamata M, Waeber C, Zhang L, Gomez-Isla T, Hyman BT, Moskowitz MA (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 18:238–247

    Article  CAS  PubMed  Google Scholar 

  • Fujimura M, Morita-Fujimura Y, Noshita N, Sugawara T, Kawase M, Chan PH (2000) The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice. J Neurosci 20:2817–2824

    Article  CAS  PubMed  Google Scholar 

  • Galluzzi L, Kepp O, Krautwald S, Kroemer G, Linkermann A (2014) Molecular mechanisms of regulated necrosis. Semin Cell Dev Biol 35:24–32. https://doi.org/10.1016/j.semcdb.2014.02.006. Epub 2014 Feb 26

    Article  PubMed  CAS  Google Scholar 

  • Grohm J, Plesnila N, Culmsee C (2010) Bid mediates fission, membrane permeabilization and peri-nuclear accumulation of mitochondria as a prerequisite for oxidative neuronal cell death. Brain Behav Immun 24:831–838

    Article  CAS  PubMed  Google Scholar 

  • Grohm J, Kim SW, Mamrak U, Tobaben S, Cassidy-Stone A, Nunnari J, Plesnila N, Culmsee C (2012) Inhibition of Drp1 provides neuroprotection in vitro and in vivo. Cell Death Differ 19:1446–1458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hussain M, Moussavi M, Korya D, Mehta S, Brar J, Chahal H, Qureshi I, Mehta T, Ahmad J, Zaidat OO, Kirmani JF (2016) Systematic review and pooled analyses of recent Neurointerventional randomized controlled trials: setting a new standard of care for acute ischemic stroke treatment after 20 years. Interv Neurol 5:39–50

    Article  PubMed  PubMed Central  Google Scholar 

  • Kilic E, Dietz GP, Hermann DM, Bahr M (2002) Intravenous TAT-Bcl-Xl is protective after middle cerebral artery occlusion in mice. Ann Neurol 52:617–622

    Article  CAS  PubMed  Google Scholar 

  • Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL (2002) The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature 419:367–374

    Article  CAS  PubMed  Google Scholar 

  • Landshamer S, Hoehn M, Barth N, Duvezin-Caubet S, Schwake G, Tobaben S, Kazhdan I, Becattini B, Zahler S, Vollmar A, Pellecchia M, Plesnila N, Wagner E, Culmsee C (2008) Bid-induced release of AIF from mitochondria causes immediate neuronal cell death. Cell Death Differ 15:1553–1563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le DA, Wu Y, Huang Z, Matsushita K, Plesnila N, Augustinack JC, Hyman BT, Yuan J, Kuida K, Flavell RA, Moskowitz MA (2002) Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci U S A 99:15188–15193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee BI, Chan PH, Kim GW (2005) Metalloporphyrin-based superoxide dismutase mimic attenuates the nuclear translocation of apoptosis-inducing factor and the subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. Stroke 36:2712–2717

    Article  CAS  PubMed  Google Scholar 

  • Lee JH, Park SY, Shin HK, Kim CD, Lee WS, Hong KW (2007) Poly(ADP-ribose) polymerase inhibition by cilostazol is implicated in the neuroprotective effect against focal cerebral ischemic infarct in rat. Brain Res 1152:182–190. Epub 2007

    Article  CAS  PubMed  Google Scholar 

  • Li X, Nemoto M, Xu Z, Yu SW, Shimoji M, Andrabi SA, Haince JF, Poirier GG, Dawson TM, Dawson VL, Koehler RC (2007) Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus. Neuroscience 144:56–65

    Article  CAS  PubMed  Google Scholar 

  • Linnik MD, Miller JA, Sprinkle-Cavallo J, Mason PJ, Thompson FY, Montgomery LR, Schroeder KK (1995) Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion. Brain Res Mol Brain Res 32:116–124

    Article  CAS  PubMed  Google Scholar 

  • Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415

    Article  CAS  PubMed  Google Scholar 

  • Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030

    Article  CAS  PubMed  Google Scholar 

  • Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, Schenkel J, Herdegen T, Debatin KM (1999) CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci 19:3809–3817

    Article  CAS  PubMed  Google Scholar 

  • Molina CA, Montaner J, Abilleira S, Ibarra B, Romero F, Arenillas JF, Alvarez-Sabin J (2001) Timing of spontaneous recanalization and risk of hemorrhagic transformation in acute cardioembolic stroke. Stroke 32:1079–1084

    Article  CAS  PubMed  Google Scholar 

  • Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668

    Article  CAS  PubMed  Google Scholar 

  • Oexler EM, Dolga A, Culmsee C (2012) AIF depletion provides neuroprotection through a preconditioning effect. Apoptosis 17:1027–1038

    Article  CAS  Google Scholar 

  • Penninger JM, Kroemer G (2003) Mitochondria, AIF and caspases-rivaling for cell death execution. Nat Cell Biol 5:97–99

    Article  CAS  PubMed  Google Scholar 

  • Plesnila N (2004) Role of mitochondrial proteins for neuronal cell death after focal cerebral ischemia. Acta Neurochir Suppl 89:15–19

    PubMed  CAS  Google Scholar 

  • Plesnila N, Zinkel S, Le DA, Amin-Hanjani S, Wu Y, Qiu J, Chiarugi A, Thomas SS, Kohane DS, Korsmeyer SJ, Moskowitz MA (2001) BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia. Proc Natl Acad Sci U S A 98:15318–15323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466

    Article  PubMed  Google Scholar 

  • Rideout HJ, Stefanis L (2001) Caspase inhibition: a potential therapeutic strategy in neurological diseases. Histol Histopathol 16:895–908

    PubMed  CAS  Google Scholar 

  • Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446

    Article  CAS  PubMed  Google Scholar 

  • Tobaben S, Grohm J, Seiler A, Conrad M, Plesnila N, Culmsee C (2011) Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons. Cell Death Differ 18:282–292

    Article  CAS  PubMed  Google Scholar 

  • Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15:135–147

    Article  CAS  Google Scholar 

  • Velier JJ, Ellison JA, Kikly KK, Spera PA, Barone FC, Feuerstein GZ (1999) Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 19:5932–5941

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, An R, Umanah GK, Park H, Nambiar K, Eacker SM, Kim B, Bao L, Harraz MM, Chang C, Chen R, Wang JE, Kam TI, Jeong JS, Xie Z, Neifert S, Qian J, Andrabi SA, Blackshaw S, Zhu H, Song H, Ming GL, Dawson VL, Dawson TM (2016) A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1. Science 354(6308)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060–2071

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wei G, Wang D, Lu H, Parmentier S, Wang Q, Panter SS, Frey WH, Ying W (2007) Intranasal administration of a PARG inhibitor profoundly decreases ischemic brain injury. Front Biosci 12:4986–4996

    Article  CAS  PubMed  Google Scholar 

  • Wiessner C, Allegrini PR, Rupalla K, Sauer D, Oltersdorf T, McGregor AL, Bischoff S, Bottiger BW, van der PH (1999) Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci Lett 268:119–122

    Article  CAS  PubMed  Google Scholar 

  • Yigitkanli K, Zheng Y, Pekcec A, Lo EH, van Leyen K (2017) Increased 12/15-Lipoxygenase leads to widespread brain injury following global cerebral ischemia. Transl Stroke Res 8:194–202

    Article  CAS  PubMed  Google Scholar 

  • Yin XM, Luo Y, Cao G, Bai L, Pei W, Kuharsky DK, Chen J (2002) Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia. J Biol Chem 277:42074–42081

    Article  CAS  PubMed  Google Scholar 

  • Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ (2000) Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 290:1761–1765

    Article  CAS  PubMed  Google Scholar 

  • Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H, Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia-ischemia in the neonatal rat brain. J Neurochem 86:306–317

    Article  CAS  PubMed  Google Scholar 

  • Zhu C, Wang X, Huang Z, Qiu L, Xu F, Vahsen N, Nilsson M, Eriksson PS, Hagberg H, Culmsee C, Plesnila N, Kroemer G, Blomgren K (2007) Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. Cell Death Differ 14:775–784

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute for Stroke and Dementia Research (ISD), University of Munich Medical Center, Munich, Germany

    Nikolaus Plesnila

  2. Clinical Pharmacy—Pharmacology and Toxicology, Faculty of Pharmacy, Philipps-University of Marburg, Marburg, Germany

    Carsten Culmsee

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  1. Nikolaus Plesnila
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  2. Carsten Culmsee
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Correspondence to Nikolaus Plesnila .

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  1. Department of Neurology, VA Greater Los Angeles Healthcare System, North Hills, California, USA

    Denson G. Fujikawa

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Plesnila, N., Culmsee, C. (2018). Involvement of Apoptosis-Inducing Factor (AIF) in Neuronal Cell Death Following Cerebral Ischemia. In: Fujikawa, D. (eds) Acute Neuronal Injury. Springer, Cham. https://doi.org/10.1007/978-3-319-77495-4_6

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