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Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies

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Abstract

Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca2+ influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

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Abbreviations

AD:

Alzheimer’s disease

CNS:

Central nervous system

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

NMDA receptor:

N-methyl-d-aspartate receptor

Aβ:

Beta amyloid

APP:

Amyloid precursor protein

CaMKII:

Calmodulin-dependent protein kinase

NFT:

Neurofibrillary tangle

NO:

Nitric oxide

PP:

Protein phosphatase

MAPK:

Mitogen-activated protein kinase

PKA:

Protein kinase

ERK:

Extracellular receptor kinase

ECD:

Excitotoxic cell death

LTD:

Depression

LTP:

Long-term potentiation

CREB:

cAMP response element-binding protein

GSK-3β:

Glycogen synthase-3β

References

  1. Gustafson DR, Skoog I, Rosengren L, Zetterberg H, Blennow K (2007) Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women. J Neurol Neurosurg Psychiatry 78:461–464

    Article  PubMed  Google Scholar 

  2. Wang Z, Yang L, Zheng H (2012) Role of APP and Abeta in synaptic physiology. Curr Alzheimer Res 9:217–226

    Article  CAS  PubMed  Google Scholar 

  3. Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590–11601

    Article  PubMed  CAS  Google Scholar 

  5. Rai S, Kamat PK, Nath C, Shukla R (2014) Glial activation and post-synaptic neurotoxicity: the key events in streptozotocin (ICV) induced memory impairment in rats. Pharmacol Biochem Behav 117:104–117

    Article  CAS  PubMed  Google Scholar 

  6. Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L (2011) Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci 31:700–711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kamat PK, Tota S, Shukla R, Ali S, Najmi AK, Nath C (2012) Mitochondrial dysfunction: a crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain. Pharmacol Biochem Behav 100:311–319

    Article  CAS  Google Scholar 

  8. Kamat PK, Rai S, Swarnkar S, Shukla R, Nath C (2014) Mechanism of synapse redox stress in okadaic acid (ICV) induced memory impairment: role of NMDA receptor. Neurochem Int. doi:10.1016/j.neuint.2014.06.012

    PubMed  Google Scholar 

  9. Rai S, Kamat PK, Nath C, Shukla R (2013) A study on neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. J Neuroimmunol 254:1–9

    Article  CAS  PubMed  Google Scholar 

  10. Kamat PK, Rai S, Swarnkar S, Shukla R, Ali S, Najmi AK, Nath C (2013) Okadaic acid-induced tau phosphorylation in rat brain: role of NMDA receptor. Neuroscience 238:97–113

    Article  CAS  PubMed  Google Scholar 

  11. Nicholls DG (2002) Mitochondrial function and dysfunction in the cell: its relevance to aging and aging-related disease. Int J Biochem Cell Biol 34:1372–1381

    Article  CAS  PubMed  Google Scholar 

  12. Farooqui AA, Yi Ong W, Lu XR, Halliwell B, Horrocks LA (2001) Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A(2) inhibitors. Brain Res Brain Res Rev 38:61–78

    Article  CAS  PubMed  Google Scholar 

  13. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1(1):a006189

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Bell KF, Bennett DA, Cuello AC (2007) Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment. J Neurosci 27:10810–10817

    Article  CAS  PubMed  Google Scholar 

  15. Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179

    Article  PubMed  Google Scholar 

  16. Cooper LN, Bear MF (2011) The BCM theory of synapse modification at 30: interaction of theory with experiment. Nat Rev Neurosci 13:798–810

    Article  CAS  Google Scholar 

  17. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791

    Article  CAS  PubMed  Google Scholar 

  18. Fetterolf F, Foster KA (2011) Regulation of long-term plasticity induction by the channel and C-terminal domains of GluN2 subunits. Mol Neurobiol 44:71–82

    Article  CAS  PubMed  Google Scholar 

  19. Lau CG, Takeuchi K, Rodenas-Ruano A, Takayasu Y, Murphy J, Bennett MV, Zukin RS (2009) Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans 37:1369–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kamat PK, Tota S, Saxena G, Shukla R, Nath C (2010) Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity. Brain Res 1309:66–74

    Article  CAS  PubMed  Google Scholar 

  21. Droge W (2002) Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants. Exp Gerontol 37:1333–1345

    Article  CAS  PubMed  Google Scholar 

  22. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    Article  CAS  PubMed  Google Scholar 

  23. Kissova I, Plamondon LT, Brisson L, Priault M, Renouf V, Schaeffer J, Camougrand N, Manon S (2006) Evaluation of the roles of apoptosis, autophagy, and mitophagy in the loss of plating efficiency induced by Bax expression in yeast. J Biol Chem 281:36187–36197

    Article  CAS  PubMed  Google Scholar 

  24. Prast H, Philippu A (2001) Nitric oxide as modulator of neuronal function. Prog Neurobiol 64:51–68

    Article  CAS  PubMed  Google Scholar 

  25. Liu D, Liu J, Sun D, Alcock NW, Wen J (2003) Spinal cord injury increases iron levels: catalytic production of hydroxyl radicals. Free Radic Biol Med 3:64–71

    Article  Google Scholar 

  26. Sachdeva R, Babbar R, Puri V, Agarwal S, Krishana B (2011) Correlation between cognitive functions and nitric oxide levels in patients with dementia. Clin EEG Neurosci 42:190–194

    Article  PubMed  Google Scholar 

  27. Chopra K, Misra S, Kuhad A (2011) Neurobiological aspects of Alzheimer’s disease. Expert Opin Ther Targets 15:535–555

    Article  CAS  PubMed  Google Scholar 

  28. Shin JH, Linden DJ (2005) An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. J Neurophysiol 94:4281–4289

    Article  CAS  PubMed  Google Scholar 

  29. Nicholls DG, Johnson-Cadwell L, Vesce S, Jekabsons M, Yadava N (2007) Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J Neurosci Res 85:3206–3212

    Article  CAS  PubMed  Google Scholar 

  30. Loh KP, Huang SH, De Silva R, Tan BK, Zhu YZ (2006) Oxidative stress: apoptosis in neuronal injury. Curr Alzheimer Res 3:327–337

    Article  CAS  PubMed  Google Scholar 

  31. Engidawork E, Gulesserian T, Yoo BC, Cairns N, Lubec G (2001) Alteration of caspases and apoptosis-related proteins in brains of patients with Alzheimer’s disease. Biochem Biophys Res Commun 281:84–93

    Article  CAS  PubMed  Google Scholar 

  32. Glazner GW, Chan SL, Lu C, Mattson MP (2000) Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J Neurosci 20:3641–3649

    CAS  PubMed  Google Scholar 

  33. Sastry PS, Rao KS (2000) Apoptosis and the nervous system. J Neurochem 74:1–20

    Article  CAS  PubMed  Google Scholar 

  34. Mattson MP, Duan W (1999) “Apoptotic” biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders. J Neurosci Res 58:152–166

    Article  CAS  PubMed  Google Scholar 

  35. D’Amelio M, Cavallucci V, Middei S, Marchetti C, Pacioni S, Ferri A, Diamantini A, De Zio D, Carrara P, Battistini L, Moreno S, Bacci A, Ammassari-Teule M, Marie H, Cecconi F (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat Neurosci 14:69–76

    Article  PubMed  CAS  Google Scholar 

  36. Louneva N, Cohen JW, Han LY, Talbot K, Wilson RS, Bennett DA, Trojanowski JQ, Arnold SE (2008) Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am J Pathol 173:1488–1495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jo J, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, Dickinson B, Scullion S, Sheng M, Collingridge G, Cho K (2011) Abeta(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci 14:545–547

    Article  CAS  PubMed  Google Scholar 

  38. Xie H, Guan J, Borrelli LA, Xu J, Serrano-Pozo A, Bacskai BJ (2013) Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model. J Neurosci 33:17042–17051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamaguchi R, Perkins G (2009) Dynamics of mitochondrial structure during apoptosis and the enigma of Opa1. Biochim Biophys Acta 1787:963–972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21:3017–3023

    CAS  PubMed  Google Scholar 

  41. Cardoso SM, Rego AC, Penacho N, Oliveira CR (2004) Apoptotic cell death induced by hydrogen peroxide in NT2 parental and mitochondrial DNA depleted cells. Neurochem Int 45:693–698

    Article  CAS  PubMed  Google Scholar 

  42. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

    Article  CAS  PubMed  Google Scholar 

  43. Zhang YQ, Herman B (2008) Expression and modification of ARC (apoptosis repressor with a CARD domain) is distinctly regulated by oxidative stress in cancer cells. J Cell Biochem 104:818–825

    Article  CAS  PubMed  Google Scholar 

  44. Zhang XD, Wang Y, Wu JC, Lin F, Han R, Han F, Fukunaga K, Qin ZH (2009) Down-regulation of Bcl-2 enhances autophagy activation and cell death induced by mitochondrial dysfunction in rat striatum. J Neurosci Res 87:3600–3610

    Article  CAS  PubMed  Google Scholar 

  45. Moreira PI, Zhu X, Wang X, Lee HG, Nunomura A, Petersen RB, Perry G, Smith MA (2009) Mitochondria: a therapeutic target in neurodegeneration. Biochim Biophys Acta 1802:212–220

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Cui H, Chen B, Chicoine LG, Nelin LD (2011) Overexpression of cationic amino acid transporter-1 increases nitric oxide production in hypoxic human pulmonary microvascular endothelial cells. Clin Exp Pharmacol Physiol 38:796–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova NN, Yang L, Starkov AA, Beal F (2011) Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J 25:4063–4072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ho AK, Terriff DL, Price DM, Wloka MT, Chik CL (2007) The role of inducible repressor proteins in the adrenergic induction of arylalkylamine-N-acetyltransferase and mitogen-activated protein kinase phosphatase-1 in rat pinealocytes. Endocrinology 148:743–751

    Article  CAS  PubMed  Google Scholar 

  49. Li X, Schulz E, Wenzel P, Munzel T, Daiber A (2014) Mitochondrial redox signaling: interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal 20:308–324

    Article  CAS  Google Scholar 

  50. Bhandari A, Holmes CP, Szardenings AK (2004) Alpha, alpha-difluoro-beta-ketophosphonates as potent inhibitors of protein tyrosine phosphatase 1B. Bioorg Med Chem Lett 14:4301–4306

    Article  PubMed  CAS  Google Scholar 

  51. Tibbles LA, Woodgett JR (1999) The stress-activated protein kinase pathways. Cell Mol Life Sci 55:1230–1254

    Article  CAS  PubMed  Google Scholar 

  52. Fuentes F, Zimmer D, Atienza M, Schottenfeld J, Penkala I, Bale T, Bence KK, Arregui CO (2012) Protein tyrosine phosphatase PTP1B is involved in hippocampal synapse formation and learning. PLoS ONE 7:e41536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Evans DB, Rank KB, Bhattacharya K, Thomsen DR, Gurney ME, Sharma SK (2000) Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau’s ability to promote microtubule assembly. J Biol Chem 275:24977–24983

    Article  CAS  PubMed  Google Scholar 

  54. Ivanov A, Pellegrino C, Rama S, Dumalska I, Salyha Y, Ben-Ari Y, Medina I (2006) Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J Physiol 572:789–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Leveille F, El Gaamouch F, Gouix E, Lecocq M, Lobner D, Nicole O, Buisson A (2008) Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 22:4258–4271

    Article  CAS  PubMed  Google Scholar 

  56. Kaufman AM, Milnerwood AJ, Sepers MD, Coquinco A, She K, Wang L, Lee H, Craig AM, Cynader M, Raymond LA (2012) Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons. J Neurosci 32:3992–4003

    Article  CAS  PubMed  Google Scholar 

  57. Zhou Q, Sheng M (2013) NMDA receptors in nervous system diseases. Neuropharmacology 74:69–75

    Article  CAS  PubMed  Google Scholar 

  58. Ramirez M, Lamas M (2009) NMDA receptor mediates proliferation and CREB phosphorylation in postnatal Muller glia-derived retinal progenitors. Mol Vis 15:713–721

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Gomperts SN, Carroll R, Malenka RC, Nicoll RA (2000) Distinct roles for ionotropic and metabotropic glutamate receptors in the maturation of excitatory synapses. J Neurosci 20:2229–2237

    CAS  PubMed  Google Scholar 

  60. Bellone C, Nicoll RA (2007) Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55:779–785

    Article  CAS  PubMed  Google Scholar 

  61. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875

    Article  CAS  PubMed  Google Scholar 

  62. Townsend M, Mehta T, Selkoe DJ (2007) Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 282:33305–33312

    Article  CAS  PubMed  Google Scholar 

  63. Wang Q, Rowan MJ, Anwyl R (2004) Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J Neurosci 24:6049–6056

    Article  CAS  PubMed  Google Scholar 

  64. Kumar A, Foster TC (2004) Enhanced long-term potentiation during aging is masked by processes involving intracellular calcium stores. J Neurophysiol 91:2437–2444

    Article  PubMed  Google Scholar 

  65. Reese LC, Zhang W, Dineley KT, Kayed R, Taglialatela G (2008) Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. Aging Cell 7:824–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 423:435–439

    Article  CAS  PubMed  Google Scholar 

  67. Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104:1433–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hansen T, Rehfeld JF, Nielsen FC (2004) GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding. Neuroreport 15:841–845

    Article  CAS  PubMed  Google Scholar 

  69. Koivisto L, Hakkinen L, Matsumoto K, McCulloch CA, Yamada KM, Larjava H (2004) Glycogen synthase kinase-3 regulates cytoskeleton and translocation of Rac1 in long cellular extensions of human keratinocytes. Exp Cell Res 293:68–80

    Article  CAS  PubMed  Google Scholar 

  70. Thornton TM, Pedraza-Alva G, Deng B, Wood CD, Aronshtam A, Clements JL, Sabio G, Davis RJ, Matthews DE, Doble B, Rincon M (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation. Science 320:667–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL (2007) LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 53:703–717

    Article  CAS  PubMed  Google Scholar 

  72. Hernandez F, Gomez de Barreda E, Fuster-Matanzo A, Lucas JJ, Avila J (2010) GSK3: a possible link between beta amyloid peptide and tau protein. Exp Neurol 223:322–325

    Article  CAS  PubMed  Google Scholar 

  73. Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR, Snider WD (2009) GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 12:1390–1397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liu GP, Zhang Y, Yao XQ, Zhang CE, Fang J, Wang Q, Wang JZ (2008) Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. Neurobiol Aging 29:1348–1358

    Article  CAS  PubMed  Google Scholar 

  75. Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000) Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20:2567–2574

    CAS  PubMed  Google Scholar 

  76. Rojo AI, Sagarra MR, Cuadrado A (2008) GSK-3beta down-regulates the transcription factor Nrf2 after oxidant damage: relevance to exposure of neuronal cells to oxidative stress. J Neurochem 105:192–202

    Article  CAS  PubMed  Google Scholar 

  77. Jouvenceau A, Dutar P (2006) A role for the protein phosphatase 2B in altered hippocampal synaptic plasticity in the aged rat. J Physiol Paris 99:154–161

    Article  CAS  PubMed  Google Scholar 

  78. Kamsler A, Segal M (2004) Hydrogen peroxide as a diffusible signal molecule in synaptic plasticity. Mol Neurobiol 29:167–178

    Article  CAS  PubMed  Google Scholar 

  79. Lin CH, Yeh SH, Leu TH, Chang WC, Wang ST, Gean PW (2003) Identification of calcineurin as a key signal in the extinction of fear memory. J Neurosci 23:1574–1579

    CAS  PubMed  Google Scholar 

  80. Serrano F, Klann E (2004) Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev 3:431–443

    Article  CAS  PubMed  Google Scholar 

  81. Chen QS, Wei WZ, Shimahara T, Xie CW (2002) Alzheimer amyloid beta-peptide inhibits the late phase of long-term potentiation through calcineurin-dependent mechanisms in the hippocampal dentate gyrus. Neurobiol Learn Mem 77:354–371

    Article  CAS  PubMed  Google Scholar 

  82. 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 276:38787–38794

    Article  CAS  PubMed  Google Scholar 

  83. Cook CN, Hejna MJ, Magnuson DJ, Lee JM (2005) Expression of calcipressin1, an inhibitor of the phosphatase calcineurin, is altered with aging and Alzheimer’s disease. J Alzheimers Dis 8:63–73

    Article  CAS  PubMed  Google Scholar 

  84. Koss DJ, Hindley KP, Riedel G, Platt B (2007) Modulation of hippocampal calcium signalling and plasticity by serine/threonine protein phosphatases. J Neurochem 102:1009–1023

    Article  CAS  PubMed  Google Scholar 

  85. Lu Y, Rosenberg PA (2007) NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors. Brain Res 1155:116–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Butterfield DA, Pocernich CB (2003) The glutamatergic system and Alzheimer’s disease: therapeutic implications. CNS Drugs 17:641–652

    Article  CAS  PubMed  Google Scholar 

  87. Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672

    Article  CAS  PubMed  Google Scholar 

  88. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D (2012) Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68:1067–1081

    Article  CAS  Google Scholar 

  89. Li YY, Cui JG, Hill JM, Bhattacharjee S, Zhao Y and Lukiw WJ (2011) Increased expression of miRNA-146a in Alzheimer’s disease transgenic mouse models. Neurosci Lett 487:94–98.

  90. McKinney RA (2010) Excitatory amino acid involvement in dendritic spine formation, maintenance and remodelling. J Physiol 588:107–116

    Article  CAS  PubMed  Google Scholar 

  91. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS (2000) PSD-95 involvement in maturation of excitatory synapses. Science 290:1364–1368

    CAS  PubMed  Google Scholar 

  92. Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, Leclerc N, Boehm J (2012) Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem 287:32040–32053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Moreno H, Choi S, Yu E, Brusco J, Avila J, Moreira JE, Sugimori M, Llinas RR (2011) Blocking effects of human tau on squid giant synapse transmission and its prevention by T-817 MA. Front Synaptic Neurosci 3:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ittner LM, Gotz J (2011) Amyloid-beta and tau—a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12:65–72

    Article  CAS  PubMed  Google Scholar 

  95. Zhang L, Li YH, Meng K, Xie W (2010) The expressions of AMPAR/GluR2 in hippocampal CA1 area of rats before and after late-phase long-term potentiation reversal. Sheng Li Xue Bao 62:23–29

    CAS  PubMed  Google Scholar 

  96. Zhang H, Wu CY, Wang W, Harrington MA (2011) Interneuronal synapses formed by motor neurons appear to be glutamatergic. Neuroreport 22:809–813

    PubMed  PubMed Central  Google Scholar 

  97. Massey PV, Johnson BE, Moult PR, Auberson YP, Brown MW, Molnar E, Collingridge GL, Bashir ZI (2004) Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24:7821–7828

    Article  CAS  PubMed  Google Scholar 

  98. Perez-Otano I, Ehlers MD (2004) Learning from NMDA receptor trafficking: clues to the development and maturation of glutamatergic synapses. Neurosignals 13:175–189

    Article  CAS  PubMed  Google Scholar 

  99. Desilva TM, Kinney HC, Borenstein NS, Trachtenberg FL, Irwin N, Volpe JJ, Rosenberg PA (2007) The glutamate transporter EAAT2 is transiently expressed in developing human cerebral white matter. J Comp Neurol 501:879–890

    Article  CAS  PubMed  Google Scholar 

  100. Ascher P, Nowak L (2009) Early biophysics of the NMDA receptor channel. J Physiol 587:4563–4564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bleich S, Sperling W, Wiltfang J, Maler JM, Kornhuber J (2003) Excitatory neurotransmission in alcoholism. Fortschr Neurol Psychiatr 71:S36–S44

    Article  PubMed  Google Scholar 

  102. Adams JP, Sweatt JD (2002) Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu Rev Pharmacol Toxicol 42:135–163

    Article  CAS  PubMed  Google Scholar 

  103. Foster TC, Kumar A (2002) Calcium dysregulation in the aging brain. Neuroscientist 8:297–301

    Article  CAS  PubMed  Google Scholar 

  104. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689

    Article  CAS  PubMed  Google Scholar 

  105. Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ (2008) Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron 59:214–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058

    Article  CAS  PubMed  Google Scholar 

  107. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Souza MA, Magni DV, Guerra GP, Oliveira MS, Furian AF, Pereira L, Marquez SV, Ferreira J, Fighera MR, Royes LF (2012) Involvement of hippocampal CAMKII/CREB signaling in the spatial memory retention induced by creatine. Amino Acids 43:2491–2503

    Article  CAS  PubMed  Google Scholar 

  109. Vierci G, Oliveira CS, Perera LR, Bornia N, Leal RB, Rossi FM (2013) CREB is modulated in the mouse superior colliculus in developmental and experimentally-induced models of plasticity. Int J Dev Neurosci 31:46–52

    Article  CAS  PubMed  Google Scholar 

  110. Bito H, Deisseroth K, Tsien RW (1996) CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell 87:1203–1214

    Article  CAS  PubMed  Google Scholar 

  111. Hardingham GE, Chawla S, Johnson CM, Bading H (1997) Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385:260–265

    Article  CAS  PubMed  Google Scholar 

  112. Vitolo OV, Sant’Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M (2002) Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci U S A 99:13217–13221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Li XY, Zhan XR, Liu XM, Wang XC (2011) CREB is a regulatory target for the protein kinase Akt/PKB in the differentiation of pancreatic ductal cells into islet beta-cells mediated by hepatocyte growth factor. Biochem Biophys Res Commun 404:711–716

    Article  CAS  PubMed  Google Scholar 

  114. Arlt S, Müller-Thomsen TM, Beisiegel U, Kontush A (2012) Effect of one-year vitamin C- and E-supplementation on cerebrospinal fluid oxidation parameters and clinical course in Alzheimer’s disease. Neurochem Res 37:2706–2714

    Article  CAS  PubMed  Google Scholar 

  115. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG et al (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69:836–841

    Article  PubMed  PubMed Central  Google Scholar 

  116. Bagi Z, Cseko C, Toth E, Koller A (2003) Oxidative stress-induced dysregulation of arteriolar wall shear stress and blood pressure in hyperhomocysteinemia is prevented by chronic vitamin C treatment. Am J Physiol Heart Circ Physiol 285:2277–2283

    Article  Google Scholar 

  117. Nadeau A, Roberge AG (1988) Effects of vitamin B12 supplementation on choline acetyltransferase activity in cat brain. Int J Vitam Nutr Res 58:402–406

    CAS  PubMed  Google Scholar 

  118. Ikeda T, Yamamoto K, Takahashi K (1992) Treatment of Alzheimer-type dementia with intravenous methylcobalamin. Clin Ther 14:426–437

    CAS  PubMed  Google Scholar 

  119. Sano M, Ernesto C, Thomas RG et al (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 336:1216–1222

    Article  CAS  PubMed  Google Scholar 

  120. Sung S, Yao Y, Uryu K et al (2004) Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer’s disease. FASEB J 18:323–325

    CAS  PubMed  Google Scholar 

  121. Nakashima H, Ishihara T, Yokota O et al (2004) Effects of α-tocopherol on an animal model of tauopathies. Free Radic Biol Med 37:176–186

    Article  CAS  PubMed  Google Scholar 

  122. Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Investig 117:236–245

    Article  CAS  PubMed  Google Scholar 

  123. Pavlik VN, Doody RS, Rountree SD, Darby EJ (2009) Vitamin E use is associated with improved survival in an Alzheimer’s disease cohort. Dement Geriatr Cogn Disord 28:536–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bolognesi ML, Bergamini C, Fato R, Oiry J, Vasseur JJ, Smietana M (2014) Synthesis of new lipoic acid conjugates and evaluation of their free radical scavenging and neuroprotective activities. Chem Biol Drug Des 83:688–696

    Article  CAS  PubMed  Google Scholar 

  125. Sancheti H, Kanamori K, Patil I, Díaz Brinton R, Ross BD, Cadenas E (2014) Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer’s disease: a 13C NMR study. J Cereb Blood Flow Metab 34:288–296

    Article  CAS  PubMed  Google Scholar 

  126. Kryscio RJ, Abner EL, Schmitt FA et al (2013) A randomized controlled Alzheimer’s disease prevention trial’s evolution into an exposure trial: the PREADViSE trial. J Nutr Health Aging 17:72–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Esposito L, Raber J, Kekonius L et al (2006) Reduction in mitochondrial superoxide dismutase modulates Alzheimer’s disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci 26:5167–5179

    Article  CAS  PubMed  Google Scholar 

  128. Rajasekar N, Dwivedi S, Tota SK, Kamat PK, Hanif K, Nath C, Shukla R (2013) Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice. Eur J Pharmacol 715:381–394

    Article  CAS  PubMed  Google Scholar 

  129. Ringman M, Cole GM, Tend E (2008) Oral curcumin for the treatment of mild-to-moderate Alzheimer’s disease: tolerability and clinical and biomarker efficacy results of a placebo-controlled 24-week study. Proceedings of the International Conference of Alzheimer’s disease Chicago, abstract.

  130. Remington R, Chan A, Paskavitz J, Shea TB (2009) Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer’s disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen 24:27–33

    Article  PubMed  Google Scholar 

  131. Chan A, Remington R, Kotyla E, Lepore A, Zemianek J, Shea TB (2010) A vitamin/nutriceutical formulation improves memory and cognitive performance in community-dwelling adults without dementia. J Nutr Health Aging 14:224–230

    Article  CAS  PubMed  Google Scholar 

  132. Gutzmann H, Hadler D (1998) Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: update on a two-year double-blind multicentre study. J Neural Transm Suppl 54:301–310

    Article  CAS  PubMed  Google Scholar 

  133. Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, Weiner MFF, Zamrini E, Thomas RG (2003) Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 61:1498–1502

    Article  CAS  PubMed  Google Scholar 

  134. Weyer G, Babej-Dölle RM, Hadler D, Hoffmann S, Hermann WM (1997) A controlled study of 2 doses of idebenone in the treatment of Alzheimer’s disease. Neuropsychobiology 36:73–82

    Article  CAS  PubMed  Google Scholar 

  135. Mulnard RA, Cotman CW, Kawas C et al (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. J Am Med Assoc 283:1007–1015

    Article  CAS  Google Scholar 

  136. Singh S, Thakur MK (2011) Gonadal steroids do not affect apolipoprotein E expression in aging mouse cerebral cortex. Cell Mol Neurobiol 31:401–405

    Article  CAS  PubMed  Google Scholar 

  137. Boldogh I, Liebenthal D, Hughes TK et al (2003) Modulation of 4HNE-mediated signaling by proline-rich peptides from ovine colostrum. J Mol Neurosci 20:125–134

    Article  CAS  PubMed  Google Scholar 

  138. Zabłocka A, Janusz M (2012) Effect of the proline-rich polypeptide complex/colostrininTM on the enzymatic antioxidant system. Arch Immunol Ther Exp 60:383–390

    Article  CAS  Google Scholar 

  139. Leszek J, Inglot AD, Janusz M et al (2002) Colostrinin proline-rich polypeptide complex fromovine colostrum—a long-term study of its efficacy in Alzheimer’s disease. Med Sci Monit 8:I93–I96

    Google Scholar 

  140. Bilikiewicz A, Gaus W (2004) Colostrinin1 (a naturally occurring proline-rich, polypeptide mixture) in the treatment of Alzheimer’s disease. J Alzheimers Dis 6:17–26

    Article  CAS  PubMed  Google Scholar 

  141. Jia N, Han K, Kong JJ, Zhang XM, Sha S, Ren GR, Cao YP (2013) (−)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. Mol Cell Biochem 380:211–218

    Article  CAS  PubMed  Google Scholar 

  142. Li SY, Wang XB, Kong LY (2014) Design, synthesis and biological evaluation of imine resveratrol derivatives as multi-targeted agents against Alzheimer’s disease. Eur J Med Chem 71:36–45

    Article  CAS  PubMed  Google Scholar 

  143. Lu C, Guo Y, Yan J, Luo Z, Luo HB, Yan M, Huang L, Li X (2013) Design, synthesis, and evaluation of multitarget-directed resveratrol derivatives for the treatment of Alzheimer’s disease. J Med Chem 56:5843–5859

    Article  CAS  PubMed  Google Scholar 

  144. Jones RW (2010) Dimebon disappointment. Alzheimers Res Ther 2:25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Steele JW, Gandy S (2013) Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy 9:617–818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bharadwaj PR, Bates KA, Porter T, Teimouri E, Perry G, Steele JW, Gandy S, Groth D, Martins RN, Verdile G (2013) Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer’s and other neurodegenerative diseases. Transl Psychiatry 3:e332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, Waichunas D, Bumgarner L, Bourdette D, Silbert L, Kaye J (2014) A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J Alzheimers Dis 38:111–120

    CAS  PubMed  Google Scholar 

  148. Hardas SS, Sultana R, Clark AM, Beckett TL, Szweda LI, Murphy MP, Butterfield DA (2013) Oxidative modification of lipoic acid by HNE in Alzheimer disease brain. Redox Biol 1:80–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Quinn JF, Bussiere JR, Hammond RS et al (2007) Chronic dietary α-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging 28:213–225

    Article  CAS  PubMed  Google Scholar 

  150. Lu P, Mamiya T, Lu LL et al (2009) Silibinin prevents amyloid b peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 157:1270–1277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Tota S, Kamat PK, Shukla R, Nath C (2011) Improvement of brain energy metabolism and cholinergic functions contributes to the beneficial effects of silibinin against streptozotocin induced memory impairment. Behav Brain Res 221:207–215

    Article  CAS  PubMed  Google Scholar 

  152. Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209:73–79

    Article  CAS  PubMed  Google Scholar 

  153. Feng Z, Zhang JT (2004) Protective effect of melatonin on β-amyloid-induced apoptosis in rat astroglioma c6 cells and its mechanism. Free Radic Biol Med 37:1790–1801

    Article  CAS  PubMed  Google Scholar 

  154. Matsubara E, Bryant-Thomas T, Quinto JP et al (2003) Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85:1101–1108

    Article  CAS  PubMed  Google Scholar 

  155. Saxena G, Bharti S, Kamat PK, Sharma S, Nath C (2010) Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pharmacol Biochem Behav 94:397–403

    Article  CAS  PubMed  Google Scholar 

  156. Prasanthi JRP, Dasari B, Marwarha G et al (2010) Caffeine protects against oxidative stress and Alzheimer’s disease-like pathology in rabbit hippocampus induced by cholesterol-enriched diet. Free Radic Biol Med 49:1212–1220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Andrieu S, Ousset PJ, Coley N, Ouzid M, Mathiex-Fortunet H, Vellas B, The GuidAge study Group (2008) GuidAge study: a 5-year double-blind, randomized trial of EGb761 for the prevention of Alzheimer’s disease in elderly subjects with memory complaints rationale, design and baseline data. Curr Alzheimer Res 5:406–415

    Article  CAS  PubMed  Google Scholar 

  158. Vellas B, Coley N, Ousset PJ et al (2012) Long-term use of standardized ginkgo biloba extract for the prevention of Alzheimer’ disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol 11:851–859

    Article  CAS  PubMed  Google Scholar 

  159. Snitz BE, O’Meara ES, Carlson MC, Arnold AM, Ives DG, Rapp SR, Saxton J, Lopez OL, Dunn LO, Sink KM, DeKosky ST, Ginkgo Evaluation of Memory (GEM) Study Investigators (2009) Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA 302:2663–2670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Saxena G, Singh SP, Pal R, Singh S, Pratap R, Nath C (2007) Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice. Pharmacol Biochem Behav 86:797–805

    Article  CAS  PubMed  Google Scholar 

  161. Niranjan R, Kamat PK, Nath C, Shukla R (2010) Evaluation of guggulipid and nimesulide on production of inflammatory mediators and GFAP expression in LPS stimulated rat astrocytoma, cell line (C6). J Ethnopharmacol 127:625–630

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the Council of Scientific and Industrial Research (CSIR), India and the National Institutes of Health, USA.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, 40202, USA

    Pradip K. Kamat, Anuradha Kalani & Neetu Tyagi

  2. Division of Pharmacology, Central Drug Research Institute (CDRI), P.O. Box 173, Lucknow, 226001, UP, India

    Shivika Rai, Santoshkumar Tota & Chandishwar Nath

  3. Scripp Institute, Jupiter, FL, 33458, USA

    Supriya Swarnkar

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  1. Pradip K. Kamat
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Kamat, P.K., Kalani, A., Rai, S. et al. Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer’s Disease: Understanding the Therapeutics Strategies. Mol Neurobiol 53, 648–661 (2016). https://doi.org/10.1007/s12035-014-9053-6

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