Neurochemical Research

, Volume 39, Issue 12, pp 2301–2312 | Cite as

Apoptosis in Alzheimer’s Disease: An Understanding of the Physiology, Pathology and Therapeutic Avenues

  • M. Obulesu
  • M. Jhansi Lakshmi


Alzheimer’s disease (AD) is a devastative neurodegenerative disorder with complex etiology. Apoptosis, a biological process that plays an essential role in normal physiology to oust a few cells and contribute to the normal growth, when impaired or influenced by various factors such as Bcl2, Bax, caspases, amyloid beta, tumor necrosis factor-α, amyloid precursor protein intracellular C-terminal domain, reactive oxygen species, perturbation of enzymes leads to deleterious neurodegenerative disorders like AD. There are diverse pathways that provoke manifold events in mitochondria and endoplasmic reticulum (ER) to execute the process of cell death. This review summarizes the crucial apoptotic mechanisms occurring in both mitochondria and ER. It gives substantial summary of the diverse mechanisms studied in vivo and in vitro. A brief account on neuroprotection of several bioactive components, flavonoids and antioxidants of plants against apoptotic events of both mitochondria and ER in both in vitro and in vivo has been discussed. In light of this, the burgeoning need to develop animal models to study the efficacy of various therapeutic effects has been accentuated.


Alzheimer’s disease Apoptosis Neuroprotection Mitochondria Endoplasmic reticulum Animal model 



Authors sincerely thank Professor Dr. Yukio Nagasaki, Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, Japan for this generous support.


  1. 1.
    Obulesu M, Rao Dowlathabad Muralidhara (2010) Animal models of Alzheimer’s disease: an understanding of pathology and therapeutic avenues. Int J Neurosci 120:531–537PubMedGoogle Scholar
  2. 2.
    Wright JW, Harding JW (2010) The brain RAS and Alzheimer’s disease. Exp Neurol 223:326–333PubMedGoogle Scholar
  3. 3.
    Obulesu M, Venu R, Somashekhar R (2011) Lipid peroxidation in Alzheimer’s disease: emphasis on metal mediated neurotoxicity. Acta Neurol Scand 124:295–301PubMedGoogle Scholar
  4. 4.
    Obulesu M, Somashekhar R, Venu R (2011) Genetics of Alzheimer’s disease: apo E and presenilins instigated neurodegeneration. Int J Neurosci 121:229–236PubMedGoogle Scholar
  5. 5.
    Obulesu M, Rao Dowlathabad Muralidhara (2010) DNA damage and impairment of DNA repair in Alzheimer’s disease. Int J Neurosci 120:397–403PubMedGoogle Scholar
  6. 6.
    Magisetty O, Rao DM, Shamasundar NM (2009) Studies on genomic DNA stability in aluminium maltolate treated aged New Zealand rabbit: relevance to the Alzheimer’s animal model. J Clin Med Res 1:212–218PubMedCentralPubMedGoogle Scholar
  7. 7.
    Obulesu M, Venu R, Somashekhar R (2011) Tau mediated neurodegeneration: an insight into Alzheimer’s disease pathology. Neurochem Res 36:1329–1335PubMedGoogle Scholar
  8. 8.
    Szewczyk B (2013) Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci 5:33PubMedCentralPubMedGoogle Scholar
  9. 9.
    Obulesu M, Jhansilakshmi M (2014) Neuroinflammation in Alzheimer’s disease: an understanding of physiology and pathology. Int J Neurosci 124:227–235PubMedGoogle Scholar
  10. 10.
    Kataoka S, Tsuruo T (1996) Apoptosis. Oncologist 1:399–401PubMedGoogle Scholar
  11. 11.
    Rathmell JC, Lindsten T, Zong WX et al (2002) Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol 3:932–939PubMedGoogle Scholar
  12. 12.
    Zapala B, Kaczynski L, Kiec-wilk B et al (2010) Humanins, the neuroprotective and cytoprotective peptides with antiapoptotic and anti-inflammatory properties. Pharmacol Rep 62:767–777PubMedGoogle Scholar
  13. 13.
    Alvarez S, Blanco S, Fresno M et al (2011) TNF-α contributes to caspase-3 independent apoptosis in neuroblastoma cells: role of NFAT. PLoS One 6:e16100PubMedCentralPubMedGoogle Scholar
  14. 14.
    Alberini CM (2009) Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89:121–145PubMedGoogle Scholar
  15. 15.
    Gatta V, Gatta D, Drago K et al (2011) Microarray analysis on human neuroblastoma cells exposed to aluminum, β(1-42)-amyloid or the β(1-42)-amyloid aluminum complex. PLoS One 6:e15965PubMedCentralPubMedGoogle Scholar
  16. 16.
    Morrison BE, Majdzadeh N, D’mello SR (2007) Histone deacetylases: focus on the nervous system. Cell Mol Life Sci 64:2258–2269PubMedGoogle Scholar
  17. 17.
    Konishi Y, Lehtinen M, Donovan N et al (2002) Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell 9:1005–1016PubMedGoogle Scholar
  18. 18.
    Lee HP, Casadesus G, Zhu X et al (2009) All-trans retinoic acid as a novel therapeutic strategy for Alzheimer’s disease. Expert Rev Neurother 9:1615–1621PubMedCentralPubMedGoogle Scholar
  19. 19.
    Radi E, Formichi P, Battisti C et al (2014) Apoptosis and oxidative stress in neurodegenerative diseases. J Alzheimers Dis 42:S125–S152Google Scholar
  20. 20.
    Menendez-Gonzalez M, Perez-Pinera P, Martinez-Rivera M et al (2011) Immunotherapy for Alzheimer’s disease: rational basis in ongoing clinical trials. Curr Pharm Des 17:508–520PubMedGoogle Scholar
  21. 21.
    Lauterbach EC, Victoroff J, Coburn KL et al (2010) Mendez, Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. J Neuropsychiatry Clin Neurosci 22:8–18PubMedGoogle Scholar
  22. 22.
    Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375PubMedGoogle Scholar
  23. 23.
    Zhang JH, Zhang Y, Herman B (2003) Caspases, apoptosis and aging. Ageing Res Rev 2:357–366PubMedGoogle Scholar
  24. 24.
    Le Bras M, Rouy I, Brenner C (2006) The modulation of inter-organelle cross-talk to control apoptosis. Med Chem 2:1–12PubMedGoogle Scholar
  25. 25.
    El-Guendy N, Rangnekar VM (2003) Apoptosis by Par-4 in cancer and neurodegenerative diseases. Exp Cell Res 283:51–66PubMedGoogle Scholar
  26. 26.
    Kim R (2005) Unknotting the roles of Bcl-2 and Bcl-xL in cell death. Biochem Biophys Res Commun 333:336–343PubMedGoogle Scholar
  27. 27.
    Hengartner MO, Bryant JA (2000) Apoptotic cell death: from worms to wombats… but what about the weeds? Symp Soc Exp Biol 52:1–12PubMedGoogle Scholar
  28. 28.
    Jahanshahi M, Nickmahzar EG, Babakordi F (2013) The effect of Ginkgo biloba extract on scopolamine-induced apoptosis in the hippocampus of rats. Anat Sci Int 88:217–222PubMedGoogle Scholar
  29. 29.
    Malik M, Fenko MD, Sheikh AM et al (2011) A novel approach for characterization of cathepsin D protease and its effect on tau and β-amyloid proteins. Neurochem Res 36:754–760PubMedGoogle Scholar
  30. 30.
    Vasileiou E, Montero RM, Turner CM et al (2010) P2X7 receptor at the heart of disease. Hippocratia 14:155–163Google Scholar
  31. 31.
    Morelli A, Chiozzi P, Chiesa A et al (2003) Extracellular ATP causes ROCK 1-dependent bleb formation in P2X7-transfected HEK293 cells. Mol Biol Cell 14:2655–2664PubMedCentralPubMedGoogle Scholar
  32. 32.
    North A (2002) Molecular physiology of P2X receptors. Physiol Rev 82:1013–1067PubMedGoogle Scholar
  33. 33.
    Chen CH, Zhou W, Liu S et al (2011) Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int J Neuropsychopharmacol 18:1–14Google Scholar
  34. 34.
    Kell DB (2010) Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples. Arch Toxicol 84:825–889PubMedCentralPubMedGoogle Scholar
  35. 35.
    Maestre C, Delgado-Esteban M, Gomez-Sanchez JC et al (2008) Cdk5 phosphorylates Cdh1 and modulates cyclin B1 stability in excitotoxicity. EMBO J 27:2736–2745PubMedCentralPubMedGoogle Scholar
  36. 36.
    Siegel RM (2006) Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 6:308–317PubMedGoogle Scholar
  37. 37.
    Shi Y (2004) Caspase activation: revisiting the induced proximity model. Cell 117:855–858PubMedGoogle Scholar
  38. 38.
    Shi Y (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 9:459–470PubMedGoogle Scholar
  39. 39.
    Sun X, Wu B, Zhang Z et al (2011) Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase 3 activation. J Biol Chem 286:9049–9062PubMedCentralPubMedGoogle Scholar
  40. 40.
    Eckert A, Marques CA, Keil U et al (2003) Increased apoptotic cell death in sporadic and genetic Alzheimer’s disease. Ann N Y Acad Sci 1010:604–609PubMedGoogle Scholar
  41. 41.
    Lakhani SA, Masud A, Kuida K et al (2006) Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311:847–851PubMedCentralPubMedGoogle Scholar
  42. 42.
    Li C, Zhao R, Gao K et al (2010) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8:67–80Google Scholar
  43. 43.
    Kim JK, Kim SH, Cho HY et al (2010) GD3 accumulation in cell surface lipid rafts prior to mitochondrial targeting contributes to amyloid-β-induced apoptosis. J Korean Med Sci 25:1492–1498PubMedCentralPubMedGoogle Scholar
  44. 44.
    Simon D, Medina M, Avila J et al (2011) Overcoming cell death and tau phosphorylation mediated by PI3KInhibition: a cell assay to measure neuroprotection. CNS Neurol Disord Drug Targets 10:208–214PubMedGoogle Scholar
  45. 45.
    Copani A, Melchiorri D, Caricasole A et al (2002) β-Amyloid induced synthesis of the ganglioside GD3 is a requisite for cell cycle reactivation and apoptosis in neurons. J Neurosci 22:3963–3968PubMedGoogle Scholar
  46. 46.
    Tillement L, Lecanu L, Papadopoulos V (2011) Further evidence on mitochondrial targeting of β-amyloid and specificity of β-amyloid-induced mitotoxicity in neurons. Neurodegener Dis 8:331–344PubMedGoogle Scholar
  47. 47.
    Gamba P, Leonarduzzi G, Tamagno E et al (2011) Interaction between 24-hydroxycholesterol, oxidative stress and amyloid-β in amplifying neuronal damage in Alzheimer’s disease: three partners in crime. Aging Cell 10:403–417PubMedGoogle Scholar
  48. 48.
    Ermak G, Morgan TE, Davies KJ (2001) Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer’s disease. J Biol Chem 276:38787–38794PubMedGoogle Scholar
  49. 49.
    Ohtsuka T, Ryu H, Minamishima YA et al (2004) ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nat Cell Biol 6:121–128PubMedGoogle Scholar
  50. 50.
    Jayanthi S, Deng X, Ladenheim B et al (2005) Cadet, Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis. Proc Natl Acad Sci USA 102:868–873PubMedCentralPubMedGoogle Scholar
  51. 51.
    Viviani B, Bartesaghi S, Corsini E et al (2004) Cytokines role in neurodegenerative events. Toxicol Lett 149:85–89PubMedGoogle Scholar
  52. 52.
    Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10:45–65PubMedGoogle Scholar
  53. 53.
    Figiel I, Dzwonek K (2007) TNF alpha and TNF receptor 1 expression in the mixed neuronal-glial cultures of hippocampal dentate gyrus exposed to glutamate or trimethyltin. Brain Res 1131:17–28PubMedGoogle Scholar
  54. 54.
    Lambertsen KL, Clausen BH, Fenger C et al (2007) Microglia and macrophages express tumor necrosis factor receptor p75 following middle cerebral artery occlusion in mice. Neuroscience 144:934–949PubMedGoogle Scholar
  55. 55.
    Ye L, Huang Y, Zhao L et al (2013) IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem 125:897–908PubMedCentralPubMedGoogle Scholar
  56. 56.
    DeChiara TM, Vejsada R, Poueymirou WT et al (1995) Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 83:313–322PubMedGoogle Scholar
  57. 57.
    Bianco F, Pravettoni E, Colombo A et al (2005) Astrocyte derived ATP induces vesicle shedding and IL-1 release from microglia. J Immunol 174:7268–7277PubMedGoogle Scholar
  58. 58.
    Chang KA, Su YH (2010) Possible roles of amyloid intracellular domain of amyloid precursor protein. BMB rep 43:656–663PubMedGoogle Scholar
  59. 59.
    Nakaya T, Suzuki T (2006) Role of APP phosphorylation in FE65-dependent gene transactivation mediated by AICD. Genes Cells 11:633–645PubMedGoogle Scholar
  60. 60.
    Nakayama K, Ohkawara T, Hiratochi M et al (2008) The intracellular domain of amyloid precursor protein induces neuron-specific apoptosis. Neurosci Lett 444:127–131PubMedGoogle Scholar
  61. 61.
    Ozaki T, Li Y, Kiruchi H et al (2006) The intracellular domain of the amyloid precursor protein (AICD) enhances the p53-mediated apoptosis. Biochem Biophys Res Commun 351:57–63PubMedGoogle Scholar
  62. 62.
    Xu Y, Kim HS, Joo Y et al (2007) Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3 beta expression. Cell Death Differ 14:79–91PubMedGoogle Scholar
  63. 63.
    Vazquez MC, Vargas LM, Inestrosa NC et al (2009) c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis. J Cell Physiol 220:136–143PubMedGoogle Scholar
  64. 64.
    Saraiva LM, da Silva GSS, Galina A et al (2010) Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria. PLoS One 5:e15230PubMedCentralPubMedGoogle Scholar
  65. 65.
    Vander Heiden MG, Plas DR, Rathmell JC et al (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21:5899–5912PubMedCentralPubMedGoogle Scholar
  66. 66.
    YamamotoY Takase K, Kishino J et al (2011) Proteomic identification of protein targets for 15-Deoxy-D12,14-Prostaglandin J2 in neuronal plasma membrane. PLoS One 6:e17552Google Scholar
  67. 67.
    Tsai FM, Shyu RY, Lin SC et al (2009) Induction of apoptosis by the retinoid inducible growth regulator RIG1 depends on the NC motif in HtTA cervical cancer cells. BMC Cell Biol 10:15PubMedCentralPubMedGoogle Scholar
  68. 68.
    Ueki S, Mahemuti G, Oyamada H et al (2008) Retinoic acids are potent inhibitors of spontaneous human eosinophil apoptosis. J Immunol 181:7689–7698PubMedGoogle Scholar
  69. 69.
    Farooqui AA, Antony P, Ong WY et al (2004) Retinoic acid-mediated phospholipase A2 signaling in the nucleus. Brain Res Brain Res Rev 45:179–195PubMedGoogle Scholar
  70. 70.
    Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631–639PubMedCentralPubMedGoogle Scholar
  71. 71.
    Moreira PI, Smith MA, Zhu X et al (2005) Oxidative stress and neurodegeneration. Ann N Y Acad Sci 1043:545–552PubMedGoogle Scholar
  72. 72.
    Rao RV, Ellerby HM, Bredesen DE (2004) Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 11:372–380PubMedGoogle Scholar
  73. 73.
    Lindholm D, Wootz H, Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13:385–392PubMedGoogle Scholar
  74. 74.
    Verkhratsky A (2005) Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev 85:201–279PubMedGoogle Scholar
  75. 75.
    LaFerla F (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3:862–872PubMedGoogle Scholar
  76. 76.
    Katayama T, Imaizumi K, Manabe T et al (2004) Tohyama, Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat 28:67–78PubMedGoogle Scholar
  77. 77.
    Hitomi J, Katayama T, Eguchi Y et al (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165:347–356PubMedCentralPubMedGoogle Scholar
  78. 78.
    Choi JH, Choi AY, Yoon H et al (2010) Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction. Exp Mol Med 42:811–822PubMedCentralPubMedGoogle Scholar
  79. 79.
    Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389PubMedGoogle Scholar
  80. 80.
    Shimoke K, Sasaya H, Ikeguchi T (2011) Analysis of the role of nerve growth factor in promoting cell survival during endoplasmic reticulum stress in PC12 cells. Methods Enzymol 490:53–70PubMedGoogle Scholar
  81. 81.
    Szegezdi E, Logue SE, Gorman AM et al (2006) Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 7:880–885PubMedCentralPubMedGoogle Scholar
  82. 82.
    Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030PubMedGoogle Scholar
  83. 83.
    Parvathinani LK, Tertysnikova S, Greco CR et al (2003) P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J Biol Chem 278:13309–13317Google Scholar
  84. 84.
    Luciano F, Zhai D, Zhu X et al (2005) Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimEL. J Biol Chem 280:15825–15835PubMedGoogle Scholar
  85. 85.
    Kariya S, Hirano M, Nagai Y et al (2003) Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches. J Mol Neurosci 25:165–169Google Scholar
  86. 86.
    Sponne I, Fifre A, Koziel V et al (2004) Humanin rescues cortical neurons from prion-peptide induced apoptosis. Mol Cell Neurosci 25:95–102PubMedGoogle Scholar
  87. 87.
    Hashimoto Y, Niikura T, Chiba T et al (2003) The cytoplasmic domain of Alzheimers amyloid-β protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2 terminal kinase-mediated neurotoxic signal via dimerization. J Pharmacol Exp Ther 306:889–902PubMedGoogle Scholar
  88. 88.
    Hashimoto Y, Kurita M, Aiso S et al (2009) Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor α/WSX-1/gp130. Mol Biol Cell 20:2864–2873PubMedCentralPubMedGoogle Scholar
  89. 89.
    Niikura T, Hashimoto Y, Tajima H et al (2003) A tripartite motif protein TRIM11 binds and destabilizes humanin, a neuroprotective peptide against Alzheimers disease relevant insults. Eur J Neurosci 17:1150–1158PubMedGoogle Scholar
  90. 90.
    Pislar AH, Kos J (2013) C-terminal peptide of γ-enolase impairs amyloid-β-induced apoptosis through p75NTR signaling. Neuromolecular Med 15:623–635PubMedGoogle Scholar
  91. 91.
    Kim IK, Lee KJ, Rhee S et al (2013) Protective effects of peroxiredoxin 6 overexpression on amyloid β-induced apoptosis in PC12 cells. Free Radic Res 47:836–846PubMedGoogle Scholar
  92. 92.
    Le Y, Gong W, Tiffany HL (2001) Amyloid β42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J Neurosci 21:RC123Google Scholar
  93. 93.
    Ramirez C, Tercero I, Pineda A et al (2011) Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment. J Alzheimers Dis 24:161–174PubMedGoogle Scholar
  94. 94.
    Li X, Darzynkiewicz Z (2000) Cleavage of poly(ADP-ribose) polymerase measured in situ in individual cells: relationship to DNA fragmentation and cell cycle position during apoptosis. Exp Cell Res 255:125–132PubMedGoogle Scholar
  95. 95.
    Song J, Park KA, Lee WT et al (2014) Apoptosis signal regulating kinase 1 (ASK1): potential as a therapeutic target for Alzheimer’s disease. Int J Mol Sci 15:2119–2129PubMedCentralPubMedGoogle Scholar
  96. 96.
    Mishra M, Heese K et al (2010) P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis. J Cell Mol Med 15:2462–2477Google Scholar
  97. 97.
    Hoarau JJ, Krejbich-Trotot MC, Jaffar-Bandjee T et al (2010) Activation and control of CNS innate immune responses in health and diseases: a balancing act finely tuned by neuroimmune regulators (NIReg). CNS Neurol Disord Drug Targets 10:25–43Google Scholar
  98. 98.
    Ha S, Furukawa R, Fechheimer M (2011) Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis. Neurobiol Aging 32:2287–2298PubMedCentralPubMedGoogle Scholar
  99. 99.
    Oules B, Del Prete D, Greco B et al (2012) Ryanodine receptor blockade reduces amyloid-β load and memory impairments in Tg2576 mouse model of Alzheimer disease. J Neurosci 32:11820–11834PubMedCentralPubMedGoogle Scholar
  100. 100.
    Chang WH, Chen CH, Gau RJ et al (2002) Effect of baicalein on apoptosis of the human Hep G2 cell line was induced by mitochondrial dysfunction. Planta Med 8:302–306Google Scholar
  101. 101.
    Wang J, Yu Y, Hashimoto F et al (2004) Baicalein induces apoptosis through ROS-mediated mitochondrial dysfunction pathway in HL-60 cells. Int J Mol Med 14:627–632PubMedGoogle Scholar
  102. 102.
    Pidgeon GP, Kandouz M, Meram A et al (2002) Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. Cancer Res 62:2721–2727PubMedGoogle Scholar
  103. 103.
    Lin HY, Shen SC, Lin CW et al (2007) Baicalein inhibition of hydrogen peroxide-induced apoptosis via ROS-dependent heme oxygenase 1 gene expression. Biochim Biophys Acta 1773:1073–1086PubMedGoogle Scholar
  104. 104.
    Li WW, Gao XM, Wang XM et al (2011) Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity. Mutat Res 708:1–10PubMedGoogle Scholar
  105. 105.
    Lu J, Wu DM, Zheng ZH et al (2011) Troxerutin protects against high cholesterol-induced cognitive deficits in mice. Brain 134:783–797PubMedGoogle Scholar
  106. 106.
    Anekonda TS (2006) Resveratrol—a boon for treating Alzheimer’s disease? Brain Res Rev 52:316–326PubMedGoogle Scholar
  107. 107.
    Lavu S, Boss O, Elliott PJ et al (2008) Sirtuins-novel therapeutic targets to treat age-associated diseases. Nat Rev Drug Discov 7:841–853PubMedGoogle Scholar
  108. 108.
    Julien C, Tremblay C, Emond V et al (2009) Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68:48–58PubMedCentralPubMedGoogle Scholar
  109. 109.
    Anekonda TS, Wadsworth TL, Sabin R et al (2011) Phytic acid as a potential treatment for Alzheimer’s pathology: evidence from animal and in vitro models. J Alzheimers Dis 23:21–35PubMedCentralPubMedGoogle Scholar
  110. 110.
    Qin W, Yang T, Ho L et al (2006) Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 281:21745–21754PubMedGoogle Scholar
  111. 111.
    Azmi NH, Azmi N, Ismail MU et al (2013) Ethyl acetate extract of germinated brown rice attenuates hydrogen peroxide-induced oxidative stress in human SH-SY5Y neuroblastoma cells: role of anti-apoptotic, pro-survival and antioxidant genes. BMC Complement Altern Med 13:177PubMedCentralPubMedGoogle Scholar
  112. 112.
    Hong SY, Jeong WS, Jun M (2012) Protective effects of the key compounds isolated from Corni fructus against β-amyloid induced neurotoxicity in PC 12 cells. Molecules 17:10831–10845PubMedGoogle Scholar
  113. 113.
    Virmani A, Pinto L, Binienda Z et al (2013) Food, nutrigenomics, and neurodegeneration—neuroprotection by what you eat! Mol Neurobiol 48:353–362PubMedGoogle Scholar
  114. 114.
    Qin W, Zhao W, Ho L et al (2008) Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer’s disease-type amyloid neuropathology and spatial memory deterioration. Ann N Y Acad Sci 1147:335–347PubMedCentralPubMedGoogle Scholar
  115. 115.
    Zhou Y, Qu ZQ, Zeng YS et al (2011) Neuroprotective effect of preadministration with Ganoderma lucidum spore on rat hippocampus. Exp Toxicol Pathol 64:673–680PubMedGoogle Scholar
  116. 116.
    Lee C, Park GH, Lee SR et al (2013) Attenuation of β-amyloid-induced oxidative cell death by sulforaphane via activation of NF-E2-related factor 2. Oxid Med Cell Longev 2013:313510PubMedCentralPubMedGoogle Scholar
  117. 117.
    Chen X, Zhang J, Chen C (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. Neuroscience 178:159–168PubMedCentralPubMedGoogle Scholar
  118. 118.
    Sakai K, Yamada M (2013) Aβ immunotherapy for Alzheimer’s disease. Brain Nerve 65:461–468PubMedGoogle Scholar
  119. 119.
    Geng J, Li M, Wu L et al (2012) Mesoporous silica nanoparticle-based H2O2 responsive controlled-release system used for Alzheimer’s disease treatment. Adv Healthc Mater 1:332–336PubMedGoogle Scholar
  120. 120.
    Sureda FX, Junyent F, Verdaguer E et al (2011) Antiapoptotic drugs: a therapeutic strategy for the prevention of neurodegenerative diseases. Curr Pharm Des 17:230–245PubMedGoogle Scholar
  121. 121.
    Cavallucci V, D’Amelio M (2011) Matter of life and death: the pharmacological approaches targeting apoptosis in brain diseases. Curr Pharm Des 17:215–229PubMedGoogle Scholar
  122. 122.
    Cui B, Li K (2013) Chronic noise exposure and Alzheimer disease: Is there an etiological association? Med Hypotheses 81:623–626PubMedGoogle Scholar
  123. 123.
    Zhang H, Wu S, Xing D (2011) YAP accelerates Aβ(25–35)-induced apoptosis through upregulation of Bax expression by interaction with p73. Apoptosis 16:808–821PubMedGoogle Scholar
  124. 124.
    Hong YK, Park SH, Lee S et al (2011) Neuroprotective effect of SuHeXiang Wan in Drosophila models of Alzheimer’s disease. J Ethnopharmacol 134:1028–1032PubMedGoogle Scholar
  125. 125.
    Obulesu M, Rao Dowlathabad Muralidhara (2011) Effect of plant extracts on Alzheimer’s disease: an insight into therapeutic avenues. J Neurosci Rural Pract 2:56–61PubMedCentralPubMedGoogle Scholar
  126. 126.
    Obulesu M, Dowlathabad MR, Bramhachari PV (2011) Carotenoids and Alzheimer’s disease: an insight into therapeutic role of retinoids in animal models. Neurochem Int 59:535–541PubMedGoogle Scholar
  127. 127.
    Kim EA, Cho CH, Hahn HG (2014) 2-Cyclopropylimino-3-methyl-1,3-thiazoline hydrochloride protects against beta-amyloid-induced activation of the apoptotic cascade in cultured cortical neurons. Cell Mol Neurobiol 34:963–972Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Materials Science, Graduate School of Pure and Applied SciencesUniversity of TsukubaTsukubaJapan
  2. 2.Department of BiochemistryCentral Food Technological Research InstituteMysoreIndia

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