Can co-activation of Nrf2 and neurotrophic signaling pathway slow Alzheimer’s disease?

International Journal of Molecular Sciences

Volumn 18, Issue 6, 2017, Pages

  Murphy, Kelsey E ^a   Park, Joshua J ^a  

^a MEDICAL COLLEGE OF OHIO   (United States)

Author keywords

Alzheimer s disease; Amyloid peptide; Mitochondrial damage; Natural products; Neurotrophic signaling pathway; Nrf2; Oxidative stress

Indexed keywords

7,8 DIHYDROXYFLAVONE; ALLICIN; AMYLOID BETA PROTEIN; APIGENIN; BRAIN DERIVED NEUROTROPHIC FACTOR; CURCUMIN; ERIODICTYOL; FIBROBLAST GROWTH FACTOR; GENISTEIN; HARPAGOSIDE; INSULIN; LUTEOLIN; NARINGENIN; NEUROTROPHIC FACTOR; ORIENTIN; PINOCEMBRINE; SOMATOMEDIN; TAURINE; THIOCTIC ACID; TOPIRAMATE; TRANSCRIPTION FACTOR NRF2; ANTIOXIDANT; NFE2L2 PROTEIN, HUMAN;

ALZHEIMER DISEASE; ANTIOXIDANT ACTIVITY; AUTOPHAGY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENDOPLASMIC RETICULUM STRESS; HUMAN; METABOLIC ACTIVATION; MOLECULAR PATHOLOGY; NEUROPROTECTION; NEUROTRANSMISSION; NONHUMAN; OXIDATIVE STRESS; PROTEIN EXPRESSION; REST; REVIEW; SYNAPTIC TRANSMISSION; ANIMAL; BRAIN; DISEASE EXACERBATION; DRUG EFFECTS; METABOLISM; NERVE CELL; PATHOLOGY; SIGNAL TRANSDUCTION;

ALZHEIMER DISEASE; ANIMALS; ANTIOXIDANTS; BRAIN; DISEASE PROGRESSION; HUMANS; NEURONS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 85020232557     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms18061168     Document Type: Review

References (231)

1. Barthet, G.; Georgakopoulos, A.; Robakis, N.K. Cellular mechanisms of-secretase substrate selection, processing and toxicity. Prog. Neurobiol. 2012, 98, 166-175. [CrossRef] [PubMed]
2. De Felice, F.G.; Velasco, P.T.; Lambert, M.P.; Viola, K.; Fernandez, S.J.; Ferreira, S.T.; Klein, W.L. Aβ 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. 2007, 282, 11590-11601. [CrossRef] [PubMed]
3. Nicholls, D.G. Mitochondrial function and dysfunction in the cell: Its relevance to aging and aging-related disease. Int. J. Biochem. Cell Biol. 2002, 34, 1372-1381. [CrossRef]
4. Ma, Q.L.; Yang, F.; Rosario, E.R.; Ubeda, O.J.; Beech, W.; Gant, D.J.; Chen, P.P.; Hudspeth, B.; Chen, C.; Zhao, Y.; et al. β-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: Suppression by omega-3 fatty acids and curcumin. J. Neurosci. 2009, 29, 9078-9089. [CrossRef] [PubMed]
5. Hong, S.; Beja-Glasser, V.F.; Nfonoyim, B.M.; Frouin, A.; Li, S.; Ramakrishnan, S.; Merry, K.M.; Shi, Q.; Rosenthal, A.; Barres, B.A.; et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 2016, 352, 712-716. [CrossRef] [PubMed]
6. Kayed, R.; Lasagna-Reeves, C.A. Molecular mechanisms of amyloid oligomers toxicity. J. Alzheimer’s Dis. 2013, 33 (Suppl. S1), S67-S78. [CrossRef] [PubMed]
7. Hsieh, H.; Boehm, J.; Sato, C.; Iwatsubo, T.; Tomita, T.; Sisodia, S.; Malinow, R. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 2006, 52, 831-843. [CrossRef] [PubMed]
8. Roselli, F.; Tirard, M.; Lu, J.; Hutzler, P.; Lamberti, P.; Livrea, P.; Morabito, M.; Almeida, O.F. Soluble β-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. J. Neurosci. 2005, 25, 11061-11070. [CrossRef] [PubMed]
9. Selkoe, D.J. Alzheimer’s disease is a synaptic failure. Science 2002, 298, 789-791. [CrossRef] [PubMed]
10. Li, S.; Hong, S.; Shepardson, N.E.;Walsh, D.M.; Shankar, G.M.; Selkoe, D. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 2009, 62, 788-801. [CrossRef] [PubMed]
11. Shankar, G.M.; Li, S.; Mehta, T.H.; Garcia-Munoz, A.; Shepardson, N.E.; Smith, I.; Brett, F.M.; Farrell, M.A.; Rowan, M.J.; Lemere, C.A.; et al. Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 2008, 14, 837-842. [CrossRef] [PubMed]
12. Moreira, P.I.; Cardoso, S.M.; Santos, M.S.; Oliveira, C.R. The key role of mitochondria in Alzheimer’s disease. J. Alzheimer’s Dis. 2006, 9, 101-110. [CrossRef]
13. Hauptmann, S.; Scherping, I.; Drose, S.; Brandt, U.; Schulz, K.L.; Jendrach, M.; Leuner, K.; Eckert, A.; Muller,W.E. Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol. Aging 2009, 30, 1574-1586. [CrossRef] [PubMed]
14. Galindo, M.F.; Ikuta, I.; Zhu, X.; Casadesus, G.; Jordan, J. Mitochondrial biology in Alzheimer’s disease pathogenesis. J. Neurochem. 2010, 114, 933-945. [CrossRef] [PubMed]
15. Mancuso, M.; Coppede, F.; Murri, L.; Siciliano, G. Mitochondrial cascade hypothesis of Alzheimer’s disease: Myth or reality? Antioxid. Redox Signal. 2007, 9, 1631-1646. [CrossRef] [PubMed]
16. David, D.C.; Hauptmann, S.; Scherping, I.; Schuessel, K.; Keil, U.; Rizzu, P.; Ravid, R.; Drose, S.; Brandt, U.; Muller, W.E.; et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J. Biol. Chem. 2005, 280, 23802-23814. [CrossRef] [PubMed]
17. Zhang,W.; Hao, J.; Liu, R.; Zhang, Z.; Lei, G.; Su, C.; Miao, J.; Li, Z. Soluble A β levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer’s disease. Behav. Brain Res. 2011, 222, 342-350. [CrossRef] [PubMed]
18. Delic, V.; Brownlow, M.; Joly-Amado, A.; Zivkovic, S.; Noble, K.; Phan, T.A.; Ta, Y.; Zhang, Y.; Bell, S.D.; Kurien, C.; et al. Calorie restriction does not restore brain mitochondrial function in P301L tau mice, but it does decrease mitochondrial F0F1-ATPase activity. Mol. Cell. Neurosci. 2015, 67, 46-54. [CrossRef] [PubMed]
19. Hansson Petersen, C.A.; Alikhani, N.; Behbahani, H.;Wiehager, B.; Pavlov, P.F.; Alafuzoff, I.; Leinonen, V.; Ito, A.; Winblad, B.; Glaser, E.; et al. The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc. Natl. Acad. Sci. USA 2008, 105, 13145-13150. [CrossRef] [PubMed]
20. Takuma, K.; Fang, F.; Zhang, W.; Yan, S.; Fukuzaki, E.; Du, H.; Sosunov, A.; McKhann, G.; Funatsu, Y.; Nakamichi, N.; et al. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction. Proc. Natl. Acad. Sci. USA 2009, 106, 20021-20026. [CrossRef] [PubMed]
21. Walther, K.A.; Grater, F.; Dougan, L.; Badilla, C.L.; Berne, B.J.; Fernandez, J.M. Signatures of hydrophobic collapse in extended proteins captured with force spectroscopy. Proc. Natl. Acad. Sci. USA 2007, 104, 7916-7921. [CrossRef] [PubMed]
22. Du, H.; Yan, S.S. Mitochondrial permeability transition pore in Alzheimer’s disease: Cyclophilin D and amyloid β. Biochim. Biophys. Acta 2010, 1802, 198-204. [CrossRef] [PubMed]
23. Lustbader, J.W.; Cirilli, M.; Lin, C.; Xu, H.W.; Takuma, K.; Wang, N.; Caspersen, C.; Chen, X.; Pollak, S.; Chaney, M.; et al. ABAD directly links A β to mitochondrial toxicity in Alzheimer’s disease. Science 2004, 304, 448-452. [CrossRef] [PubMed]
24. Cha, M.Y.; Han, S.H.; Son, S.M.; Hong, H.S.; Choi, Y.J.; Byun, J.; Mook-Jung, I. Mitochondria-specific accumulation of amyloid β induces mitochondrial dysfunction leading to apoptotic cell death. PLoS ONE 2012, 7, e34929. [CrossRef] [PubMed]
25. Casley, C.S.; Canevari, L.; Land, J.M.; Clark, J.B.; Sharpe, M.A. β-Amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J. Neurochem. 2002, 80, 91-100. [CrossRef] [PubMed]
26. Manczak, M.; Anekonda, T.S.; Henson, E.; Park, B.S.; Quinn, J.; Reddy, P.H. Mitochondria are a direct site of A β accumulation in Alzheimer’s disease neurons: Implications for free radical generation and oxidative damage in disease progression. Hum. Mol. Genet. 2006, 15, 1437-1449. [CrossRef] [PubMed]
27. Caspersen, C.;Wang, N.; Yao, J.; Sosunov, A.; Chen, X.; Lustbader, J.W.; Xu, H.W.; Stern, D.; McKhann, G.; Yan, S.D. Mitochondrial A β: A potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J. 2005, 19, 2040-2041. [PubMed]
28. Kim, T.S.; Pae, C.U.; Yoon, S.J.; Jang, W.Y.; Lee, N.J.; Kim, J.J.; Lee, S.J.; Lee, C.; Paik, I.H.; Lee, C.U. Decreased plasma antioxidants in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry 2006, 21, 344-348. [CrossRef] [PubMed]
29. Ghosh, D.; LeVault, K.R.; Barnett, A.J.; Brewer, G.J. A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3xTg-AD mouse neurons. J. Neurosci. 2012, 32, 5821-5832. [CrossRef] [PubMed]
30. Aguilar, T.A.; Navarro, B.C.; Pérez, J.A. Endogenous Antioxidants: A Review of their Role in Oxidative Stress. In A Master Regulator of Oxidative Stress-The Transcription Factor Nrf2; InTech: Rijeka, Croatia, 2016; pp. 3-19.
31. Araújo, R.F.; Martins, D.B.; Borba, M.A. Oxidative Stress and Disease. In A Master Regulator of Oxidative Stress-The Transcription Factor Nrf2; InTech: Rijeka, Croatia, 2016; pp. 185-199.
32. Halliwell, B. Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment. Drugs Aging 2001, 18, 685-716. [CrossRef] [PubMed]
33. Patten, D.A.; Germain, M.; Kelly, M.A.; Slack, R.S. Reactive oxygen species: Stuck in the middle of neurodegeneration. J. Alzheimer’s Dis. 2010, 20 (Suppl. S2), S357-S367. [CrossRef] [PubMed]
34. Toledo, J.C., Jr.; Augusto, O. Connecting the chemical and biological properties of nitric oxide. Chem. Res. Toxicol. 2012, 25, 975-989. [CrossRef] [PubMed]
35. Cui, H.; Chen, B.; Chicoine, L.G.; Nelin, L.D. Overexpression of cationic amino acid transporter-1 increases nitric oxide production in hypoxic human pulmonary microvascular endothelial cells. Clin. Exp. Pharmacol. Physiol. 2011, 38, 796-803. [CrossRef] [PubMed]
36. Adibhatla, R.M.; Hatcher, J.F. Lipid oxidation and peroxidation in CNS health and disease: From molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signal. 2010, 12, 125-169. [CrossRef] [PubMed]
37. Hensley, K.; Maidt, M.L.; Yu, Z.; Sang, H.; Markesbery, W.R.; Floyd, R.A. Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J. Neurosci. 1998, 18, 8126-8132. [PubMed]
38. Smith, M.A.; Sayre, L.M.; Anderson, V.E.; Harris, P.L.; Beal, M.F.; Kowall, N.; Perry, G. Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine. J. Histochem. Cytochem. 1998, 46, 731-735. [CrossRef] [PubMed]
39. Nunomura, A.; Perry, G.; Pappolla, M.A.; Wade, R.; Hirai, K.; Chiba, S.; Smith, M.A. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J. Neurosci. 1999, 19, 1959-1964. [PubMed]
40. Hensley, K.; Hall, N.; Subramaniam, R.; Cole, P.; Harris, M.; Aksenov, M.; Aksenova, M.; Gabbita, S.P.; Wu, J.F.; Carney, J.M.; et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J. Neurochem. 1995, 65, 2146-2156. [CrossRef] [PubMed]
41. Lyras, L.; Cairns, N.J.; Jenner, A.; Jenner, P.; Halliwell, B. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J. Neurochem. 1997, 68, 2061-2069. [CrossRef] [PubMed]
42. Smith, M.A.; Richey Harris, P.L.; Sayre, L.M.; Beckman, J.S.; Perry, G.Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci. 1997, 17, 2653-2657. [PubMed]
43. Marcus, D.L.; Thomas, C.; Rodriguez, C.; Simberkoff, K.; Tsai, J.S.; Strafaci, J.A.; Freedman, M.L. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp. Neurol. 1998, 150, 40-44. [CrossRef] [PubMed]
44. Ansari, M.A.; Scheff, S.W. Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J. Neuropathol. Exp. Neurol. 2010, 69, 155-167. [CrossRef] [PubMed]
45. Lucassen, P.J.; Chung,W.C.; Kamphorst,W.; Swaab, D.F. DNA damage distribution in the human brain as shown by in situ end labeling; area-specific differences in aging and Alzheimer disease in the absence of apoptotic morphology. J. Neuropathol. Exp. Neurol. 1997, 56, 887-900. [CrossRef] [PubMed]
46. Butterfield, D.A.; Poon, H.F.; St Clair, D.; Keller, J.N.; Pierce, W.M.; Klein, J.B.; Markesbery, W.R. Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: Insights into the development of Alzheimer’s disease. Neurobiol. Dis. 2006, 22, 223-232. [CrossRef] [PubMed]
47. Williams, T.I.; Lynn, B.C.; Markesbery, W.R.; Lovell, M.A. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease. Neurobiol. Aging 2006, 27, 1094-1109. [CrossRef] [PubMed]
48. Yao, Y.; Zhukareva, V.; Sung, S.; Clark, C.M.; Rokach, J.; Lee, V.M.; Trojanowski, J.Q.; Pratico, D. Enhanced brain levels of 8,12-iso-iPF2α-VI differentiate AD from frontotemporal dementia. Neurology 2003, 61, 475-478. [CrossRef] [PubMed]
49. Nakagawa, T.; Zhu, H.; Morishima, N.; Li, E.; Xu, J.; Yankner, B.A.; Yuan, J. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 2000, 403, 98-103. [CrossRef] [PubMed]
50. Schroder, M.; Kaufman, R.J. ER stress and the unfolded protein response. Mutat. Res. 2005, 569, 29-63. [CrossRef] [PubMed]
51. Harding, H.P.; Zhang, Y.; Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999, 397, 271-274. [PubMed]
52. Novoa, I.; Zeng, H.; Harding, H.P.; Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J. Cell Biol. 2001, 153, 1011-1022. [CrossRef] [PubMed]
53. Ameri, K.; Harris, A.L. Activating transcription factor 4. Int. J. Biochem. Cell Biol. 2008, 40, 14-21. [CrossRef] [PubMed]
54. Hetz, C. The unfolded protein response: Controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 2012, 13, 89-102. [CrossRef] [PubMed]
55. Yoshida, H.; Matsui, T.; Yamamoto, A.; Okada, T.; Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001, 107, 881-891. [CrossRef]
56. Calfon, M.; Zeng, H.; Urano, F.; Till, J.H.; Hubbard, S.R.; Harding, H.P.; Clark, S.G.; Ron, D. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002, 415, 92-96. [CrossRef] [PubMed]
57. Hollien, J.; Lin, J.H.; Li, H.; Stevens, N.; Walter, P.; Weissman, J.S. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 2009, 186, 323-331. [CrossRef] [PubMed]
58. Ye, J.; Rawson, R.B.; Komuro, R.; Chen, X.; Dave, U.P.; Prywes, R.; Brown, M.S.; Goldstein, J.L. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 2000, 6, 1355-1364. [CrossRef]
59. Okada, T.; Yoshida, H.; Akazawa, R.; Negishi, M.; Mori, K. Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response. Biochem. J. 2002, 366 Pt 2, 585-594. [CrossRef] [PubMed]
60. Yoshida, H.; Haze, K.; Yanagi, H.; Yura, T.; Mori, K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J. Biol. Chem. 1998, 273, 33741-33749. [CrossRef] [PubMed]
61. Han, J.; Back, S.H.; Hur, J.; Lin, Y.H.; Gildersleeve, R.; Shan, J.; Yuan, C.L.; Krokowski, D.; Wang, S.; Hatzoglou, M.; et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 2013, 15, 481-490. [CrossRef] [PubMed]
62. Szegezdi, E.; Logue, S.E.; Gorman, A.M.; Samali, A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006, 7, 880-885. [CrossRef] [PubMed]
63. Shore, G.C.; Papa, F.R.; Oakes, S.A. Signaling cell death from the endoplasmic reticulum stress response. Curr. Opin. Cell Biol. 2011, 23, 143-149. [CrossRef] [PubMed]
64. Urra, H.; Dufey, E.; Lisbona, F.; Rojas-Rivera, D.; Hetz, C. When ER stress reaches a dead end. Biochim. Biophys. Acta 2013, 1833, 3507-3517. [CrossRef] [PubMed]
65. Er, E.; Oliver, L.; Cartron, P.F.; Juin, P.; Manon, S.; Vallette, F.M. Mitochondria as the target of the pro-apoptotic protein Bax. Biochim. Biophys. Acta 2006, 1757, 1301-1311. [CrossRef] [PubMed]
66. Oh, K.J.; Singh, P.; Lee, K.; Foss, K.; Lee, S.; Park, M.; Lee, S.; Aluvila, S.; Park, M.; Singh, P.; et al. Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3-BH3 contact interface in BAK homo-oligomers. J. Biol. Chem. 2010, 285, 28924-28937. [CrossRef] [PubMed]
67. Zhang, D.; Armstrong, J.S. Bax and the mitochondrial permeability transition cooperate in the release of cytochrome c during endoplasmic reticulum-stress-induced apoptosis. Cell Death Differ. 2007, 14, 703-715. [CrossRef] [PubMed]
68. Brush, M.H.;Weiser, D.C.; Shenolikar, S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 α to the endoplasmic reticulum and promotes dephosphorylation of the α subunit of eukaryotic translation initiation factor 2. Mol. Cell. Biol. 2003, 23, 1292-1303. [CrossRef] [PubMed]
69. Kojima, E.; Takeuchi, A.; Haneda, M.; Yagi, A.; Hasegawa, T.; Yamaki, K.; Takeda, K.; Akira, S.; Shimokata, K.; Isobe, K. The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: Elucidation by GADD34-deficient mice. FASEB J. 2003, 17, 1573-1575. [CrossRef] [PubMed]
70. McCullough, K.D.; Martindale, J.L.; Klotz, L.O.; Aw, T.Y.; Holbrook, N.J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. 2001, 21, 1249-1259. [CrossRef] [PubMed]
71. Li, G.; Mongillo, M.; Chin, K.T.; Harding, H.; Ron, D.; Marks, A.R.; Tabas, I. Role of ERO1-α-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J. Cell Biol. 2009, 186, 783-792. [CrossRef] [PubMed]
72. Timmins, J.M.; Ozcan, L.; Seimon, T.A.; Li, G.; Malagelada, C.; Backs, J.; Backs, T.; Bassel-Duby, R.; Olson, E.N.; Anderson, M.E.; Tabas, I. Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways. J. Clin. Investig. 2009, 119, 2925-2941. [CrossRef] [PubMed]
73. Tabas, I.; Ron, D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat. Cell Biol. 2011, 13, 184-190. [CrossRef] [PubMed]
74. Urano, F.; Wang, X.; Bertolotti, A.; Zhang, Y.; Chung, P.; Harding, H.P.; Ron, D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000, 287, 664-666. [CrossRef] [PubMed]
75. Yoneda, T.; Imaizumi, K.; Oono, K.; Yui, D.; Gomi, F.; Katayama, T.; Tohyama, M. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J. Biol. Chem. 2001, 276, 13935-13940. [CrossRef] [PubMed]
76. Nishitoh, H.; Matsuzawa, A.; Tobiume, K.; Saegusa, K.; Takeda, K.; Inoue, K.; Hori, S.; Kakizuka, A.; Ichijo, H. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002, 16, 1345-1355. [CrossRef] [PubMed]
77. Hoozemans, J.J.; van Haastert, E.S.; Nijholt, D.A.; Rozemuller, A.J.; Eikelenboom, P.; Scheper,W. The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am. J. Pathol. 2009, 174, 1241-1251. [CrossRef] [PubMed]
78. Roussel, B.D.; Kruppa, A.J.; Miranda, E.; Crowther, D.C.; Lomas, D.A.; Marciniak, S.J. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013, 12, 105-118. [CrossRef]
79. Hoozemans, J.J.; Veerhuis, R.; Van Haastert, E.S.; Rozemuller, J.M.; Baas, F.; Eikelenboom, P.; Scheper, W. The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol. 2005, 110, 165-172. [CrossRef] [PubMed]
80. Honjo, Y.; Ito, H.; Horibe, T.; Takahashi, R.; Kawakami, K. Protein disulfide isomerase-immunopositive inclusions in patients with Alzheimer disease. Brain Res. 2010, 1349, 90-96. [CrossRef] [PubMed]
81. Costa-Mattioli, M.; Gobert, D.; Stern, E.; Gamache, K.; Colina, R.; Cuello, C.; Sossin, W.; Kaufman, R.; Pelletier, J.; Rosenblum, K.; et al. eIF2α Phosphorylation bidirectionally regulates the switch from short-to long-term synaptic plasticity and memory. Cell 2007, 129, 195-206. [CrossRef] [PubMed]
82. Stern, E.; Chinnakkaruppan, A.; David, O.; Sonenberg, N.; Rosenblum, K. Blocking the eIF2α kinase (PKR) enhances positive and negative forms of cortex-dependent taste memory. J. Neurosci. 2013, 33, 2517-2525. [CrossRef] [PubMed]
83. Di Prisco, G.V.; Huang,W.; Buffington, S.A.; Hsu, C.C.; Bonnen, P.E.; Placzek, A.N.; Sidrauski, C.; Krnjevic, K.; Kaufman, R.J.; Walter, P.; et al. Translational control of mGluR-dependent long-term depression and object-place learning by eIF2α. Nat. Neurosci. 2014, 17, 1073-1082. [CrossRef] [PubMed]
84. Jiang, Z.; Belforte, J.E.; Lu, Y.; Yabe, Y.; Pickel, J.; Smith, C.B.; Je, H.S.; Lu, B.; Nakazawa, K. eIF2α Phosphorylation-dependent translation in CA1 pyramidal cells impairs hippocampal memory consolidation without affecting general translation. J. Neurosci. 2010, 30, 2582-2594. [CrossRef] [PubMed]
85. O’Connor, T.; Sadleir, K.R.; Maus, E.; Velliquette, R.A.; Zhao, J.; Cole, S.L.; Eimer, W.A.; Hitt, B.; Bembinster, L.A.; Lammich, S.; et al. Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 2008, 60, 988-1009. [CrossRef] [PubMed]
86. Sakagami, Y.; Kudo, T.; Tanimukai, H.; Kanayama, D.; Omi, T.; Horiguchi, K.; Okochi, M.; Imaizumi, K.; Takeda, M. Involvement of endoplasmic reticulum stress in tauopathy. Biochem. Biophys. Res. Commun. 2013, 430, 500-504. [CrossRef] [PubMed]
87. Ogata, M.; Hino, S.; Saito, A.; Morikawa, K.; Kondo, S.; Kanemoto, S.; Murakami, T.; Taniguchi, M.; Tanii, I.; Yoshinaga, K.; et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell Biol. 2006, 26, 9220-9231. [CrossRef] [PubMed]
88. Ulamek-Koziol, M.; Furmaga-Jablonska,W.; Januszewski, S.; Brzozowska, J.; Scislewska, M.; Jablonski, M.; Pluta, R. Neuronal autophagy: Self-eating or self-cannibalism in Alzheimer’s disease. Neurochem. Res. 2013, 38, 1769-1773. [CrossRef] [PubMed]
89. Shimobayashi, M.; Hall, M.N. Making new contacts: The mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 2014, 15, 155-162. [CrossRef] [PubMed]
90. Mizushima, N. The role of the Atg1/ULK1 complex in autophagy regulation. Curr. Opin. Cell Biol. 2010, 22, 132-139. [CrossRef] [PubMed]
91. Maiese, K.; Chong, Z.Z.; Wang, S.; Shang, Y.C. Oxidant stress and signal transduction in the nervous system with the PI 3-K, Akt, and mTOR cascade. Int. J. Mol. Sci. 2012, 13, 13830-13866. [CrossRef] [PubMed]
92. Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 2011, 13, 132-141. [CrossRef] [PubMed]
93. Hayashi-Nishino, M.; Fujita, N.; Noda, T.; Yamaguchi, A.; Yoshimori, T.; Yamamoto, A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 2009, 11, 1433-1437. [CrossRef] [PubMed]
94. Mizushima, N.; Noda, T.; Ohsumi, Y. Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J. 1999, 18, 3888-3896. [CrossRef] [PubMed]
95. Yu, Z.Q.; Ni, T.; Hong, B.; Wang, H.Y.; Jiang, F.J.; Zou, S.; Chen, Y.; Zheng, X.L.; Klionsky, D.J.; Liang, Y.; et al. Dual roles of Atg8-PE deconjugation by Atg4 in autophagy. Autophagy 2012, 8, 883-892. [CrossRef] [PubMed]
96. Weidberg, H.; Shvets, E.; Shpilka, T.; Shimron, F.; Shinder, V.; Elazar, Z. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. EMBO J. 2010, 29, 1792-1802. [CrossRef] [PubMed]
97. Ichimura, Y.; Kumanomidou, T.; Sou, Y.S.; Mizushima, T.; Ezaki, J.; Ueno, T.; Kominami, E.; Yamane, T.; Tanaka, K.; Komatsu, M. Structural basis for sorting mechanism of p62 in selective autophagy. J. Biol. Chem. 2008, 283, 22847-22857. [CrossRef] [PubMed]
98. C, O.N. PI3-kinase/Akt/mTOR signaling: Impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp. Gerontol. 2013, 48, 647-653.
99. Caccamo, A.; Majumder, S.; Richardson, A.; Strong, R.; Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and Tau: Effects on cognitive impairments. J. Biol. Chem. 2010, 285, 13107-13120. [CrossRef] [PubMed]
100. Spilman, P.; Podlutskaya, N.; Hart, M.J.; Debnath, J.; Gorostiza, O.; Bredesen, D.; Richardson, A.; Strong, R.; Galvan, V. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer’s disease. PLoS ONE 2010, 5, e9979. [CrossRef] [PubMed]
101. Zhu, Z.; Yan, J.; Jiang,W.; Yao, X.G.; Chen, J.; Chen, L.; Li, C.; Hu, L.; Jiang, H.; Shen, X. Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both β-amyloid production and clearance. J. Neurosci. 2013, 33, 13138-13149. [CrossRef] [PubMed]
102. Hamano, T.; Gendron, T.F.; Causevic, E.; Yen, S.H.; Lin, W.L.; Isidoro, C.; Deture, M.; Ko, L.W. Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur. J. Neurosci. 2008, 27, 1119-1130. [CrossRef] [PubMed]
103. Caccamo, A.; De Pinto, V.; Messina, A.; Branca, C.; Oddo, S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer’s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J. Neurosci. 2014, 34, 7988-7998. [CrossRef] [PubMed]
104. Zhang, M.; An, C.; Gao, Y.; Leak, R.K.; Chen, J.; Zhang, F. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog. Neurobiol. 2013, 100, 30-47. [CrossRef] [PubMed]
105. Lo Gerfo, A.; Petrozzi, L.; Chico, L.; Siciliano, G. Nrf2 Signaling: An Adaptive Response Pathway for Neurodegenerative Disorders. In A Master Regulator of Oxidative Stress-The Transcription Factor Nrf2; InTech: Rijeka, Croatia, 2016; pp. 145-166.
106. Johnson, D.A.; Johnson, J.A. Nrf2-A therapeutic target for the treatment of neurodegenerative diseases. Free Radic. Biol. Med. 2015, 88 Pt B, 253-267. [CrossRef] [PubMed]
107. Kobayashi, A.; Kang, M.I.; Okawa, H.; Ohtsuji, M.; Zenke, Y.; Chiba, T.; Igarashi, K.; Yamamoto, M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol. Cell. Biol. 2004, 24, 7130-7139. [CrossRef] [PubMed]
108. Scapagnini, G.; Vasto, S.; Abraham, N.G.; Caruso, C.; Zella, D.; Fabio, G. Modulation of Nrf2/ARE pathway by food polyphenols: A nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol. Neurobiol. 2011, 44, 192-201. [CrossRef] [PubMed]
109. Calkins, M.J.; Johnson, D.A.; Townsend, J.A.; Vargas, M.R.; Dowell, J.A.; Williamson, T.P.; Kraft, A.D.; Lee, J.M.; Li, J.; Johnson, J.A. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid. Redox Signal. 2009, 11, 497-508. [CrossRef] [PubMed]
110. De Vries, H.E.; Witte, M.; Hondius, D.; Rozemuller, A.J.; Drukarch, B.; Hoozemans, J.; van Horssen, J. Nrf2-induced antioxidant protection: A promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radic. Biol. Med. 2008, 45, 1375-1383. [CrossRef] [PubMed]
111. Yenki, P.; Khodagholi, F.; Shaerzadeh, F. Inhibition of phosphorylation of JNK suppresses Aβ-induced ER stress and upregulates prosurvival mitochondrial proteins in rat hippocampus. J. Mol. Neurosci. 2013, 49, 262-269. [CrossRef] [PubMed]
112. Miyamoto, N.; Izumi, H.; Miyamoto, R.; Kondo, H.; Tawara, A.; Sasaguri, Y.; Kohno, K. Quercetin induces the expression of peroxiredoxins 3 and 5 via the Nrf2/NRF1 transcription pathway. Investig. Ophthalmol. Vis. Sci. 2011, 52, 1055-1063. [CrossRef] [PubMed]
113. Maines, M.D.; Trakshel, G.M.; Kutty, R.K. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J. Biol. Chem. 1986, 261, 411-419. [PubMed]
114. Schipper, H.M. Heme oxygenase-1: Role in brain aging and neurodegeneration. Exp. Gerontol. 2000, 35, 821-830. [CrossRef]
115. Barone, E.; Di Domenico, F.; Sultana, R.; Coccia, R.; Mancuso, C.; Perluigi, M.; Butterfield, D.A. Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment. Free Radic. Biol. Med. 2012, 52, 2292-2301. [CrossRef] [PubMed]
116. Zhang, L.; Yu, H.; Zhao, X.; Lin, X.; Tan, C.; Cao, G.; Wang, Z. Neuroprotective effects of salidroside against β-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Neurochem. Int. 2010, 57, 547-555. [CrossRef] [PubMed]
117. Maines, M.D. The heme oxygenase system: A regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 517-554. [CrossRef] [PubMed]
118. Kapitulnik, J.; Maines, M.D. Pleiotropic functions of biliverdin reductase: Cellular signaling and generation of cytoprotective and cytotoxic bilirubin. Trends Pharmacol. Sci. 2009, 30, 129-137. [CrossRef] [PubMed]
119. Dore, S.; Snyder, S.H. Neuroprotective action of bilirubin against oxidative stress in primary hippocampal cultures. Ann. N. Y. Acad. Sci. 1999, 890, 167-172. [CrossRef] [PubMed]
120. Takeda, A.; Itoyama, Y.; Kimpara, T.; Zhu, X.; Avila, J.; Dwyer, B.E.; Perry, G.; Smith, M.A. Heme catabolism and heme oxygenase in neurodegenerative disease. Antioxid. Redox Signal. 2004, 6, 888-894. [CrossRef] [PubMed]
121. Barone, E.; Di Domenico, F.; Mancuso, C.; Butterfield, D.A. The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: It’s time for reconciliation. Neurobiol. Dis. 2014, 62, 144-159. [CrossRef] [PubMed]
122. Okado-Matsumoto, A.; Fridovich, I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J. Biol. Chem. 2001, 276, 38388-38393. [CrossRef] [PubMed]
123. Ma, T.; Hoeffer, C.A.; Wong, H.; Massaad, C.A.; Zhou, P.; Iadecola, C.; Murphy, M.P.; Pautler, R.G.; Klann, E. Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide. J. Neurosci. 2011, 31, 5589-5595. [CrossRef] [PubMed]
124. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem. J. 2009, 417, 1-13. [CrossRef] [PubMed]
125. Esposito, L.; Raber, J.; Kekonius, L.; Yan, F.; Yu, G.Q.; Bien-Ly, N.; Puolivali, J.; Scearce-Levie, K.; Masliah, E.; Mucke, L. 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. 2006, 26, 5167-5179. [CrossRef] [PubMed]
126. Li, F.; Calingasan, N.Y.; Yu, F.; Mauck, W.M.; Toidze, M.; Almeida, C.G.; Takahashi, R.H.; Carlson, G.A.; Flint Beal, M.; Lin, M.T.; et al. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J. Neurochem. 2004, 89, 1308-1312. [CrossRef] [PubMed]
127. Dumont, M.;Wille, E.; Stack, C.; Calingasan, N.Y.; Beal, M.F.; Lin, M.T. Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer’s disease. FASEB J. 2009, 23, 2459-2466. [CrossRef] [PubMed]
128. Massaad, C.A.;Washington, T.M.; Pautler, R.G.; Klann, E. Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2009, 106, 13576-13581. [CrossRef] [PubMed]
129. Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787-795. [CrossRef] [PubMed]
130. Ferrer-Sueta, G.; Radi, R. Chemical biology of peroxynitrite: Kinetics, diffusion, and radicals. ACS Chem. Biol. 2009, 4, 161-177. [CrossRef] [PubMed]
131. Holmgren, A.; Lu, J. Thioredoxin and thioredoxin reductase: Current research with special reference to human disease. Biochem. Biophys. Res. Commun. 2010, 396, 120-124. [CrossRef] [PubMed]
132. Lillig, C.H.; Berndt, C.; Holmgren, A. Glutaredoxin systems. Biochim. Biophys. Acta 2008, 1780, 1304-1317. [CrossRef] [PubMed]
133. Strange, R.C.; Spiteri, M.A.; Ramachandran, S.; Fryer, A.A. Glutathione-S-transferase family of enzymes. Mutat. Res. 2001, 482, 21-26. [CrossRef]
134. Ramsey, C.P.; Glass, C.A.; Montgomery, M.B.; Lindl, K.A.; Ritson, G.P.; Chia, L.A.; Hamilton, R.L.; Chu, C.T.; Jordan-Sciutto, K.L. Expression of Nrf2 in neurodegenerative diseases. J. Neuropathol. Exp. Neurol. 2007, 66, 75-85. [CrossRef] [PubMed]
135. Joshi, G.; Johnson, J.A. The Nrf2-ARE pathway: A valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Pat. CNS Drug Discov. 2012, 7, 218-229. [CrossRef] [PubMed]
136. Joshi, G.; Gan, K.A.; Johnson, D.A.; Johnson, J.A. Increased Alzheimer’s disease-like pathology in the APP/PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol. Aging 2015, 36, 664-679. [CrossRef] [PubMed]
137. Kanninen, K.; Malm, T.M.; Jyrkkanen, H.K.; Goldsteins, G.; Keksa-Goldsteine, V.; Tanila, H.; Yamamoto, M.; Yla-Herttuala, S.; Levonen, A.L.; Koistinaho, J. Nuclear factor erythroid 2-related factor 2 protects against β amyloid. Mol. Cell. Neurosci. 2008, 39, 302-313. [CrossRef] [PubMed]
138. Ghosh, D.; LeVault, K.R.; Brewer, G.J. Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species. Neurobiol. Aging 2014, 35, 179-190. [CrossRef] [PubMed]
139. Dumont, M.; Wille, E.; Calingasan, N.Y.; Tampellini, D.; Williams, C.; Gouras, G.K.; Liby, K.; Sporn, M.; Nathan, C.; Flint Beal, M.; et al. Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer’s disease. J. Neurochem. 2009, 109, 502-512. [CrossRef] [PubMed]
140. Gan, L.; Vargas, M.R.; Johnson, D.A.; Johnson, J.A. Astrocyte-specific overexpression of Nrf2 delays motor pathology and synuclein aggregation throughout the CNS in the α-synuclein mutant (A53T) mouse model. J. Neurosci. 2012, 32, 17775-17787. [CrossRef] [PubMed]
141. Im, J.Y.; Lee, K.W.; Woo, J.M.; Junn, E.; Mouradian, M.M. DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum. Mol. Genet. 2012, 21, 3013-3024. [CrossRef] [PubMed]
142. Ren, H.; Fu, K.; Wang, D.; Mu, C.; Wang, G. Oxidized DJ-1 interacts with the mitochondrial protein BCL-XL. J. Biol. Chem. 2011, 286, 35308-35317. [CrossRef] [PubMed]
143. Zhou, W.; Zhu, M.; Wilson, M.A.; Petsko, G.A.; Fink, A.L. The oxidation state of DJ-1 regulates its chaperone activity toward α-synuclein. J. Mol. Biol. 2006, 356, 1036-1048. [CrossRef] [PubMed]
144. Benito, E.; Barco, A. CREB’s control of intrinsic and synaptic plasticity: Implications for CREB-dependent memory models. Trends Neurosci. 2010, 33, 230-240. [CrossRef] [PubMed]
145. Barco, A.; Marie, H. Genetic approaches to investigate the role of CREB in neuronal plasticity and memory. Mol. Neurobiol. 2011, 44, 330-349. [CrossRef] [PubMed]
146. Lee, J.; Kim, C.H.; Simon, D.K.; Aminova, L.R.; Andreyev, A.Y.; Kushnareva, Y.E.; Murphy, A.N.; Lonze, B.E.; Kim, K.S.; Ginty, D.D.; et al. Mitochondrial cyclic AMP response element-binding protein (CREB) mediates mitochondrial gene expression and neuronal survival. J. Biol. Chem. 2005, 280, 40398-40401. [CrossRef] [PubMed]
147. Satoh, Y.; Kobayashi, Y.; Takeuchi, A.; Pages, G.; Pouyssegur, J.; Kazama, T. Deletion of ERK1 and ERK2 in the CNS causes cortical abnormalities and neonatal lethality: Erk1 deficiency enhances the impairment of neurogenesis in Erk2-deficient mice. J. Neurosci. 2011, 31, 1149-1155. [CrossRef] [PubMed]
148. Parmar, M.S.; Jaumotte, J.D.; Wyrostek, S.L.; Zigmond, M.J.; Cavanaugh, J.E. Role of ERK1, 2, and 5 in dopamine neuron survival during aging. Neurobiol. Aging 2014, 35, 669-679. [CrossRef] [PubMed]
149. Hetman, M.; Gozdz, A. Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. Eur. J. Biochem. 2004, 271, 2050-2055. [CrossRef] [PubMed]
150. Cowansage, K.K.; LeDoux, J.E.; Monfils, M.H. Brain-derived neurotrophic factor: A dynamic gatekeeper of neural plasticity. Curr. Mol. Pharmacol. 2010, 3, 12-29. [CrossRef] [PubMed]
151. Minichiello, L. TrkB signalling pathways in LTP and learning. Nat. Rev. Neurosci. 2009, 10, 850-860. [CrossRef] [PubMed]
152. Jiang, X.; Tian, F.; Mearow, K.; Okagaki, P.; Lipsky, R.H.; Marini, A.M. The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. J. Neurochem. 2005, 94, 713-722. [CrossRef] [PubMed]
153. Kaplan, D.R.; Miller, F.D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 2000, 10, 381-391. [CrossRef]
154. Patapoutian, A.; Reichardt, L.F. Trk receptors: Mediators of neurotrophin action. Curr. Opin. Neurobiol. 2001, 11, 272-280. [CrossRef]
155. Beck, T.; Lindholm, D.; Castren, E.; Wree, A. Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus. J. Cereb. Blood Flow Metab. 1994, 14, 689-692. [CrossRef] [PubMed]
156. Schabitz,W.R.; Sommer, C.; Zoder,W.; Kiessling, M.; Schwaninger, M.; Schwab, S. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke 2000, 31, 2212-2217. [CrossRef] [PubMed]
157. Almeida, R.D.; Manadas, B.J.; Melo, C.V.; Gomes, J.R.; Mendes, C.S.; Graos, M.M.; Carvalho, R.F.; Carvalho, A.P.; Duarte, C.B. Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ. 2005, 12, 1329-1343. [CrossRef] [PubMed]
158. Murer, M.G.; Yan, Q.; Raisman-Vozari, R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog. Neurobiol. 2001, 63, 71-124. [CrossRef]
159. Michalski, B.; Fahnestock, M. Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Res. Mol. Brain Res. 2003, 111, 148-154. [CrossRef]
160. Peng, S.; Wuu, J.; Mufson, E.J.; Fahnestock, M. Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J. Neurochem. 2005, 93, 1412-1421. [CrossRef] [PubMed]
161. Christensen, R.; Marcussen, A.B.; Wortwein, G.; Knudsen, G.M.; Aznar, S. A β (1-42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT(2A) levels. Exp. Neurol. 2008, 210, 164-171. [CrossRef] [PubMed]
162. Peng, S.; Garzon, D.J.; Marchese, M.; Klein, W.; Ginsberg, S.D.; Francis, B.M.; Mount, H.T.; Mufson, E.J.; Salehi, A.; Fahnestock, M. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 2009, 29, 9321-9329. [CrossRef] [PubMed]
163. Zuccato, C.; Cattaneo, E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 2009, 5, 311-322. [CrossRef] [PubMed]
164. Stockhorst, U.; de Fries, D.; Steingrueber, H.J.; Scherbaum, W.A. Insulin and the CNS: Effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol. Behav. 2004, 83, 47-54. [CrossRef]
165. Hoyer, S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur. J. Pharmacol. 2004, 490, 115-125. [CrossRef] [PubMed]
166. Benedict, C.; Hallschmid, M.; Hatke, A.; Schultes, B.; Fehm, H.L.; Born, J.; Kern, W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004, 29, 1326-1334. [CrossRef] [PubMed]
167. Zhao, W.; Chen, H.; Xu, H.; Moore, E.; Meiri, N.; Quon, M.J.; Alkon, D.L. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J. Biol. Chem. 1999, 274, 34893-34902. [CrossRef] [PubMed]
168. Freude, S.; Schilbach, K.; Schubert, M. The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer’s disease: From model organisms to human disease. Curr. Alzheimer Res. 2009, 6, 213-323. [CrossRef] [PubMed]
169. De la Monte, S.M.;Wands, J.R. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer’s disease. J. Alzheimer’s Dis. 2005, 7, 45-61. [CrossRef]
170. Plum, L.; Schubert, M.; Bruning, J.C. The role of insulin receptor signaling in the brain. Trends Endocrinol. Metab. 2005, 16, 59-65. [CrossRef] [PubMed]
171. Shankar, G.M.; Bloodgood, B.L.; Townsend, M.; Walsh, D.M.; Selkoe, D.J.; Sabatini, B.L. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 2007, 27, 2866-2875. [CrossRef] [PubMed]
172. Horwood, J.M.; Dufour, F.; Laroche, S.; Davis, S. Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur. J. Neurosci. 2006, 23, 3375-3384. [CrossRef] [PubMed]
173. Condorelli, F.; Salomoni, P.; Cotteret, S.; Cesi, V.; Srinivasula, S.M.; Alnemri, E.S.; Calabretta, B. Caspase cleavage enhances the apoptosis-inducing effects of BAD. Mol. Cell Biol. 2001, 21, 3025-3036. [CrossRef] [PubMed]
174. Halestrap, A.P.; Doran, E.; Gillespie, J.P.; O’Toole, A. Mitochondria and cell death. Biochem. Soc. Trans. 2000, 28, 170-177. [CrossRef] [PubMed]
175. Zhao, L.; Teter, B.; Morihara, T.; Lim, G.P.; Ambegaokar, S.S.; Ubeda, O.J.; Frautschy, S.A.; Cole, G.M. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: Implications for Alzheimer’s disease intervention. J. Neurosci. 2004, 24, 11120-11126. [CrossRef] [PubMed]
176. Farris, W.; Mansourian, S.; Chang, Y.; Lindsley, L.; Eckman, E.A.; Frosch, M.P.; Eckman, C.B.; Tanzi, R.E.; Selkoe, D.J.; Guenette, S. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc. Natl. Acad. Sci. USA 2003, 100, 4162-4167. [CrossRef] [PubMed]
177. Watson, G.S.; Peskind, E.R.; Asthana, S.; Purganan, K.;Wait, C.; Chapman, D.; Schwartz, M.W.; Plymate, S.; Craft, S. Insulin increases CSF A β 42 levels in normal older adults. Neurology 2003, 60, 1899-1903. [CrossRef] [PubMed]
178. Dudek, H.; Datta, S.R.; Franke, T.F.; Birnbaum, M.J.; Yao, R.; Cooper, G.M.; Segal, R.A.; Kaplan, D.R.; Greenberg, M.E. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997, 275, 661-665. [CrossRef] [PubMed]
179. Banks, W.A.; Dohgu, S.; Lynch, J.L.; Fleegal-DeMotta, M.A.; Erickson, M.A.; Nakaoke, R.; Vo, T.Q. Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier. Endocrinology 2008, 149, 1514-1523. [CrossRef] [PubMed]
180. Reger, M.A.; Watson, G.S.; Frey, W.H., 2nd; Baker, L.D.; Cholerton, B.; Keeling, M.L.; Belongia, D.A.; Fishel, M.A.; Plymate, S.R.; Schellenberg, G.D.; et al. Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype. Neurobiol. Aging 2006, 27, 451-458. [CrossRef] [PubMed]
181. Dhamoon, M.S.; Noble, J.M.; Craft, S. Intranasal insulin improves cognition and modulates β-amyloid in early AD. Neurology 2009, 72, 292-293. [CrossRef] [PubMed]
182. Peltier, J.; O’Neill, A.; Schaffer, D.V. PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev. Neurobiol. 2007, 67, 1348-1361. [CrossRef] [PubMed]
183. Soto, I.; Rosenthal, J.J.; Blagburn, J.M.; Blanco, R.E. Fibroblast growth factor 2 applied to the optic nerve after axotomy up-regulates BDNF and TrkB in ganglion cells by activating the ERK and PKA signaling pathways. J. Neurochem. 2006, 96, 82-96. [CrossRef] [PubMed]
184. Barraud, P.; He, X.; Zhao, C.; Caldwell, M.A.; Franklin, R.J. FGF but not EGF induces phosphorylation of the cAMP response element binding protein in olfactory mucosa-derived cell cultures. Exp. Cell Res. 2010, 316, 1489-1499. [CrossRef] [PubMed]
185. Vargas, M.R.; Pehar, M.; Cassina, P.; Martinez-Palma, L.; Thompson, J.A.; Beckman, J.S.; Barbeito, L. Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: Consequences for motor neuron survival. J. Biol. Chem. 2005, 280, 25571-25579. [CrossRef] [PubMed]
186. Huang, J.Y.; Chuang, J.I. Fibroblast growth factor 9 upregulates heme oxygenase-1 and-glutamylcysteine synthetase expression to protect neurons from 1-methyl-4-phenylpyridinium toxicity. Free Radic. Biol. Med. 2010, 49, 1099-1108. [CrossRef] [PubMed]
187. Chuang, J.I.; Huang, J.Y.; Tsai, S.J.; Sun, H.S.; Yang, S.H.; Chuang, P.C.; Huang, B.M.; Ching, C.H. FGF9-induced changes in cellular redox status and HO-1 upregulation are FGFR-dependent and proceed through both ERK and AKT to induce CREB and Nrf2 activation. Free Radic. Biol. Med. 2015, 89, 274-286. [CrossRef] [PubMed]
188. Zeldich, E.; Chen, C.D.; Colvin, T.A.; Bove-Fenderson, E.A.; Liang, J.; Tucker Zhou, T.B.; Harris, D.A.; Abraham, C.R. The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J. Biol. Chem. 2014, 289, 24700-24715. [CrossRef] [PubMed]
189. Anderson, A.A.; Kendal, C.E.; Garcia-Maya, M.; Kenny, A.V.; Morris-Triggs, S.A.; Wu, T.; Reynolds, R.; Hohenester, E.; Saffell, J.L. A peptide from the first fibronectin domain of NCAM acts as an inverse agonist and stimulates FGF receptor activation, neurite outgrowth and survival. J. Neurochem. 2005, 95, 570-583. [CrossRef] [PubMed]
190. Moosavi, F.; Hosseini, R.; Saso, L.; Firuzi, O. Modulation of neurotrophic signaling pathways by polyphenols. Drug Des. Dev. Ther. 2016, 10, 23-42.
191. Wang, Y.; Gao, J.; Miao, Y.; Cui, Q.; Zhao, W.; Zhang, J.; Wang, H. Pinocembrin protects SH-SY5Y cells against MPP+-induced neurotoxicity through the mitochondrial apoptotic pathway. J. Mol. Neurosci. 2014, 53, 537-545. [CrossRef] [PubMed]
192. Gao, M.; Liu, R.; Zhu, S.Y.; Du, G.H. Acute neurovascular unit protective action of pinocembrin against permanent cerebral ischemia in rats. J. Asian Nat. Prod. Res. 2008, 10, 551-558. [CrossRef] [PubMed]
193. Liu, R.; Wu, C.X.; Zhou, D.; Yang, F.; Tian, S.; Zhang, L.; Zhang, T.T.; Du, G.H. Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med. 2012, 10, 105. [CrossRef] [PubMed]
194. Shi, L.L.; Chen, B.N.; Gao, M.; Zhang, H.A.; Li, Y.J.;Wang, L.; Du, G.H. The characteristics of therapeutic effect of pinocembrin in transient global brain ischemia/reperfusion rats. Life Sci. 2011, 88, 521-528. [CrossRef] [PubMed]
195. Meng, F.; Liu, R.; Gao, M.; Wang, Y.; Yu, X.; Xuan, Z.; Sun, J.; Yang, F.; Wu, C.; Du, G. Pinocembrin attenuates blood-brain barrier injury induced by global cerebral ischemia-reperfusion in rats. Brain Res. 2011, 1391, 93-101. [CrossRef] [PubMed]
196. Jin, X.; Liu, Q.; Jia, L.; Li, M.;Wang, X. Pinocembrin attenuates 6-OHDA-induced neuronal cell death through Nrf2/ARE pathway in SH-SY5Y cells. Cell. Mol. Neurobiol. 2015, 35, 323-333. [CrossRef] [PubMed]
197. Heo, H.J.; Kim, D.O.; Shin, S.C.; Kim, M.J.; Kim, B.G.; Shin, D.H. Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection. J. Agric. Food Chem. 2004, 52, 1520-1525. [CrossRef] [PubMed]
198. Zbarsky, V.; Datla, K.P.; Parkar, S.; Rai, D.K.; Aruoma, O.I.; Dexter, D.T. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson’s disease. Free Radic. Res. 2005, 39, 1119-1125. [CrossRef] [PubMed]
199. Lou, H.; Jing, X.; Wei, X.; Shi, H.; Ren, D.; Zhang, X. Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology 2014, 79, 380-388. [CrossRef] [PubMed]
200. Linford, N.J.; Dorsa, D.M. 17β-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin. Steroids 2002, 67, 1029-1040. [CrossRef]
201. Schreihofer, D.A.; Redmond, L. Soy phytoestrogens are neuroprotective against stroke-like injury in vitro. Neuroscience 2009, 158, 602-609. [CrossRef] [PubMed]
202. Wang, R.; Tu, J.; Zhang, Q.; Zhang, X.; Zhu, Y.; Ma, W.; Cheng, C.; Brann, D.W.; Yang, F. Genistein attenuates ischemic oxidative damage and behavioral deficits via eNOS/Nrf2/HO-1 signaling. Hippocampus 2013, 23, 634-647. [CrossRef] [PubMed]
203. Yu, L.; Wang, S.; Chen, X.; Yang, H.; Li, X.; Xu, Y.; Zhu, X. Orientin alleviates cognitive deficits and oxidative stress in A β 1-42-induced mouse model of Alzheimer’s disease. Life Sci. 2015, 121, 104-109. [CrossRef] [PubMed]
204. Jing, X.; Shi, H.; Zhu, X.; Wei, X.; Ren, M.; Han, M.; Ren, D.; Lou, H. Eriodictyol Attenuates β-Amyloid 25-35 Peptide-Induced Oxidative Cell Death in Primary Cultured Neurons by Activation of Nrf2. Neurochem. Res. 2015, 40, 1463-1471. [CrossRef] [PubMed]
205. Kang, S.S.; Lee, J.Y.; Choi, Y.K.; Kim, G.S.; Han, B.H. Neuroprotective effects of flavones on hydrogen peroxide-induced apoptosis in SH-SY5Y neuroblostoma cells. Bioorg. Med. Chem. Lett. 2004, 14, 2261-2264. [CrossRef] [PubMed]
206. Cheng, H.Y.; Hsieh, M.T.; Tsai, F.S.; Wu, C.R.; Chiu, C.S.; Lee, M.M.; Xu, H.X.; Zhao, Z.Z.; Peng, W.H. Neuroprotective effect of luteolin on amyloid β protein (25-35)-induced toxicity in cultured rat cortical neurons. Phytother. Res. 2010, 24 (Suppl. S1), S102-S108. [CrossRef] [PubMed]
207. Lin, C.W.;Wu, M.J.; Liu, I.Y.; Su, J.D.; Yen, J.H. Neurotrophic and cytoprotective action of luteolin in PC12 cells through ERK-dependent induction of Nrf2-driven HO-1 expression. J. Agric. Food Chem. 2010, 58, 4477-4486. [CrossRef] [PubMed]
208. Han, J.Y.; Ahn, S.Y.; Kim, C.S.; Yoo, S.K.; Kim, S.K.; Kim, H.C.; Hong, J.T.; Oh, K.W. Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol. Pharm. Bull. 2012, 35, 1440-1446. [CrossRef] [PubMed]
209. Zhao, L.;Wang, J.L.; Liu, R.; Li, X.X.; Li, J.F.; Zhang, L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules 2013, 18, 9949-9965. [CrossRef] [PubMed]
210. Tian, M.; Zeng, Y.; Hu, Y.; Yuan, X.; Liu, S.; Li, J.; Lu, P.; Sun, Y.; Gao, L.; Fu, D.; et al. 7,8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome. Neuropharmacology 2015, 89, 43-53. [CrossRef] [PubMed]
211. Gao, L.; Tian, M.; Zhao, H.Y.; Xu, Q.Q.; Huang, Y.M.; Si, Q.C.; Tian, Q.; Wu, Q.M.; Hu, X.M.; Sun, L.B.; McClintock, S.M.; Zeng, Y. TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer’s disease. J. Neurochem. 2016, 136, 620-636. [CrossRef] [PubMed]
212. Jang, S.W.; Liu, X.; Yepes, M.; Shepherd, K.R.; Miller, G.W.; Liu, Y.; Wilson, W.D.; Xiao, G.; Blanchi, B.; Sun, Y.E.; et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc. Natl. Acad. Sci. USA 2010, 107, 2687-2692. [CrossRef] [PubMed]
213. Qin, X.Y.; Cheng, Y.; Yu, L.C. Potential protection of curcumin against intracellular amyloid β-induced toxicity in cultured rat prefrontal cortical neurons. Neurosci. Lett. 2010, 480, 21-24. [CrossRef] [PubMed]
214. Begum, A.N.; Jones, M.R.; Lim, G.P.; Morihara, T.; Kim, P.; Heath, D.D.; Rock, C.L.; Pruitt, M.A.; Yang, F.; Hudspeth, B.; et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J. Pharmacol. Exp. Ther. 2008, 326, 196-208. [CrossRef] [PubMed]
215. Zhang, L.; Fang, Y.; Xu, Y.; Lian, Y.; Xie, N.; Wu, T.; Zhang, H.; Sun, L.; Zhang, R.; Wang, Z. Curcumin improves amyloid β-peptide (1-42) induced spatial memory deficits through BDNF-ERK signaling pathway. PLoS ONE 2015, 10, e0131525. [CrossRef] [PubMed]
216. Pinkaew, D.; Changtam, C.; Tocharus, C.; Thummayot, S.; Suksamrarn, A.; Tocharus, J. Di-O-demethylcurcumin protects SK-N-SH cells against mitochondrial and endoplasmic reticulum-mediated apoptotic cell death induced by Aβ25-35. Neurochem. Int. 2015, 80, 110-119. [CrossRef] [PubMed]
217. Yang, Y.; Shuaib, A.; Li, Q.; Siddiqui, M.M. Neuroprotection by delayed administration of topiramate in a rat model of middle cerebral artery embolization. Brain Res. 1998, 804, 169-176. [CrossRef]
218. Niebauer, M.; Gruenthal, M. Topiramate reduces neuronal injury after experimental status epilepticus. Brain Res. 1999, 837, 263-269. [CrossRef]
219. Mao, X.Y.; Cao, Y.G.; Ji, Z.; Zhou, H.H.; Liu, Z.Q.; Sun, H.L. Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons. Prog. Neuropsychopharmacol. Biol. Psychiatry 2015, 60, 11-17. [CrossRef] [PubMed]
220. Jeong, E.J.; Lee, K.Y.; Kim, S.H.; Sung, S.H.; Kim, Y.C. Cognitive-enhancing and antioxidant activities of iridoid glycosides from Scrophularia buergeriana in scopolamine-treated mice. Eur. J. Pharmacol. 2008, 588, 78-84. [CrossRef] [PubMed]
221. Li, J.; Ding, X.; Zhang, R.; Jiang, W.; Sun, X.; Xia, Z.; Wang, X.; Wu, E.; Zhang, Y.; Hu, Y. Harpagoside ameliorates the amyloid-β-induced cognitive impairment in rats via up-regulating BDNF expression and MAPK/PI3K pathways. Neuroscience 2015, 303, 103-114. [CrossRef] [PubMed]
222. Leon, R.; Wu, H.; Jin, Y.; Wei, J.; Buddhala, C.; Prentice, H.; Wu, J.Y. Protective function of taurine in glutamate-induced apoptosis in cultured neurons. J. Neurosci. Res. 2009, 87, 1185-1194. [CrossRef] [PubMed]
223. Jia, N.; Sun, Q.; Su, Q.; Dang, S.; Chen, G. Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1α pathway. Redox Biol. 2016, 10, 179-190. [CrossRef] [PubMed]
224. Cao, P.J.; Jin, Y.J.; Li, M.E.; Zhou, R.; Yang, M.Z. PGC-1α may associated with the anti-obesity effect of taurine on rats induced by arcuate nucleus lesion. Nutr. Neurosci. 2016, 19, 86-93. [CrossRef] [PubMed]
225. Nagai, K.; Fukuno, S.; Oda, A.; Konishi, H. Protective effects of taurine on doxorubicin-induced acute hepatotoxicity through suppression of oxidative stress and apoptotic responses. Anticancer Drugs 2016, 27, 17-23. [CrossRef] [PubMed]
226. Scarpulla, R.C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 2011, 1813, 1269-1278. [CrossRef] [PubMed]
227. Packer, L.; Roy, S.; Sen, C.K. α-Lipoic acid: A metabolic antioxidant and potential redox modulator of transcription. Adv. Pharmacol. 1997, 38, 79-101. [PubMed]
228. Koriyama, Y.; Nakayama, Y.; Matsugo, S.; Kato, S. Protective effect of lipoic acid against oxidative stress is mediated by Keap1/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cellline. Brain Res. 2013, 1499, 145-157. [CrossRef] [PubMed]
229. Li, X.H.; Li, C.Y.; Xiang, Z.G.; Zhong, F.; Chen, Z.Y.; Lu, J.M. Allicin can reduce neuronal death and ameliorate the spatial memory impairment in Alzheimer’s disease models. Neurosciences 2010, 15, 237-243. [PubMed]
230. Zhu, Y.F.; Li, X.H.; Yuan, Z.P.; Li, C.Y.; Tian, R.B.; Jia,W.; Xiao, Z.P. Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway. Eur. J. Pharmacol. 2015, 762, 239-246. [CrossRef] [PubMed]
231. Petersen, R.C.; Thomas, R.G.; Grundman, M.; Bennett, D.; Doody, R.; Ferris, S.; Galasko, D.; Jin, S.; Kaye, J.; Levey, A.; et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N. Engl. J. Med. 2005, 352, 2379-2388. [CrossRef] [PubMed]