Reviews and Monographs

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Αίγλη Παπαφιλίππου
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1 Reviews and Monographs Progress in Biochemistry and Biophysics 2012, 39(8): 756~763 wwwpibbaccn (AD), AD, AD,, AD AD * ** ( ) (AD) β- β- AD AD β- (Aβ) β- R74 DOI: /SPJ (Alzheimer's disease AD) ROS [1 2] RNS Fenton [3 4] [5] [7] [7] [8 9] [10 11] [12] [13] [14] AD (NO) O 2 NO O 2 ONOO - β- (β-amyloid Aβ) AD Aβ ROS RNS 1 * ( , ) ** Tel: , zhaobl@sun5ibpaccn (ROS) (RNS)

2 2012; 39 (8), 757 Ca 2+ [18 21] 8- ) Aβ SH-SY5Y [22] ROS ( ) ROS SOD( ) c caspases ROS [22] [15] AD [23 24] AD AD [25 26] AD Aβ [16] [27 28] - Aβ O 2 β- AD 2 AD AD AD DNA DNA DNA AD ( (APP) ) APP Aβ Aβ [17] AD AD APP APP AD APP APP ROS AD [29 30] APP [31 33] APP (CAT) (SOD) ( ) Cu + Fe ( APP

3 758 Prog Biochem Biophys 2012; 39 (8) 30 AD [34 35] [41] AD APP APP AD [36] [42] AD AD 21(IL-21) 2C(iprotenkinase2C, PKC) APP Aβ β2 (TGF2β) APP AD APP AD (MCI) AD β- APP β- AD β- (catalase) [37] AD APP Aβ Aβ (ICP-OES) AD APP ROS β- a - APP mrna 5 IRE IRP1 [38 39] Duce b APP c APP β- [40] APP β- AD 50 mg/l (FAC) AD APP AD APP 100 mg/l FAC Aβ APP APP APP FAC APP [39] Aβ [43] AD 2005 Zlokovic c

4 2012; 39 (8), 759 [44] AD [50] ( 8- ) AD AD [15] (Tf) (TfR) Aβ Tf-TfR Tf-TfR (10-4 mol/l) Aβ DMT1 Aβ Fe 2+ Zn 2+ Mn 2+ Co 2+ Cd 2+ Cu 2+ Aβ Ni 2+ Pb 2+ [51] Tf-TfR TfR sod-1 TfR prdx-2 skn-1 TfR [17] Aβ TfR AD [39] [52] Aβ TfR Aβ SH-SY5Y APP/PS1 AD [53] AD DMT1 (ferritin) ferritin 3 AD O 2 H 2 O 2 O 2 [45] AD H 2 O 2 AD β- (Hb) [46] Aβ Fenton APP Aβ ROS AD (iron regulatory protein IRP) AD AD RNA 3 5 [47] (iron responsive element IRE) [48] IRP Fe-S Aβ IRP IRE TfR mrna TfR mrna IRP IRE APP Aβ AD Aβ Cu 2+ Cu + Fe 3+ Fe 2+ [49] Cu + Fe 2+

5 760 Prog Biochem Biophys 2012; 39 (8) (ferroportin) (Fe-regulated transporter 1 IREG1) (metal transport protein 1 MTP1) (ceruloplasmin CP) Aβ CP Aβ 75% hsp-60 hsp-162 ctl-2 Aβ Aβ APP Aβ(1~42) (APPsw Swedish mutation) SH-SY5Y Aβ APPsw skn-12 APPsw hsp-60 hsp-162 [28] APPsw ctl-2 APPsw [54] APPsw (TfR) AD SOD 4 Aβ Aβ (C elegans) Aβ CL2006 N2 [22] APPsw O 2 Aβ NO O 2 (AD) Aβ NO Aβ NO APPv717I NO CA1 [55] (10-3 mol/l) Aβ SH-SY5Y 8 Aβ Aβ Aβ X Aβ Aβ [57 62] Aβ 25~35 8 Aβ 4 Aβ 25~35 Aβ 25~35 Aβ 25~35 Aβ caspase-3 CuZn-sod prdx-2 Aβ 25~35 [56] Mn-sod (40 μmol/l) (10-3 mol/l) 4 Aβ (01 μmol/l)

6 2012; 39 (8), 761 [21] APPsw SH-SY5Y Aβ (FPP) FPP Aβ ROS Aβ [28] , 53(12): [4] Tong Z Q, Zhang J L, Luo W H, et al Urine formaldehyde level is inversely correlated to mini mental state examination scores in senile dementia Neurobiology of Aging, 2011, 32(1): [5] Zhou J W Recent progress in neurodegenerative disorder research in China Sci China Life Sci, 2010, 53(3): [6] Liu Y Y, Qiang M, Wei Y, et al A novel molecular mechanism for nitrated α-synuclein-induced cell death J Molecular Cell Biology, 2011, 3(4): [7],,, Tau DNA, 2011, 38(12): Lu J, Miao J Y, Pan R, et al Prog Biochem Biophys, 2011, 38(12): AD AD AD Sci, 2010, 53(3): Aβ ( 1) 53(3): AD [8] Zhang X H, Poo M M Progress in neural plasticity Sci China Life [9] Luo Z G Synapse formation and remodeling Axon guidance and neuronal migration research in China Sci China Life Sci, 2010, [10] Zhang M, Zhao Z M, He L, et al A meta-analysis of oxidative stress markers in schizophrenia Sci China Life Sci, 2010, 53 (1): [11] Sun P, Zhang Q, Han J Y, et al TLR4 signaling induced TLR2 expression in the process of mimic cerebral ischemia/reperfusion in vitro Sci China Life Sci, 2010, 53(2): [12] Wang Y Z, Xu T L Ion channels in neuronal survival Sci China Life Sci, 2010, 53(3): [13],,, Aβ, 2010, 37(2): Liu L L, Sheng B Y, Gong K, et al Prog Biochem Biophys, 2010, 37(2): [14] Luo Y F, Zhang J, Liu N Q, et al Copper ions influence the toxicity of β-amyloid (1-42) in a concentration-dependent manner in a AD AD Caenorhabditis elegans model of Alzheimer's disease Sci China Life Sci, 2011, 54(6): Fig 1 Relation of Mental metabolic homeostasis and AD [15] Zhao B L Natural antioxidants for neurodegenerative diseases Mol Neurobiol, 2005, 31(2): AD [16] Stohs S J, Bagchi D Oxidative mechanisms in the toxicity of metal AD ions Free Radic Biol Med, 1995, 18(3): AD [17] Huang X, Atwood C S, Hartshorn M A, et al The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through AD AD metal ion reduction Biochemistry, 1999, 38(13): [18] Smith M A, Perry G, Richey P L, et al Oxidative damage in Alzheimer's Nature, 1996, 382(2): [19] Sayre L M, Zelasko D A, Harris P L, et al 4-Hydroxynonenalderived advanced lipid peroxidation end products are increased in [1] Goedert M, Ghetti B Alois Alzheimer: his life and times Brain Pathol, 2007, 17(1): Alzheimer's disease J Neurochem, 1997, 68(11): [20] Nunomura A, Perry G, Pappolla M A, et al RNA oxidation is a [2] Vickers J C, Dickson T C, Adlard P A, et al The cause of neuronal degeneration in Alzheimer's disease Prog Neurobiol, 2000, 60(2): prominent feasure of vulnerable neurons in Alzheimer's disease J Neurosci, 1999, 19(10): [21] Zeng H, Chen Q, Zhao B L Genistein ameliorated β-amyloid [3] He R Q, Lu J, Miao J Y Formaldehyde stress Sci China Life Sci,

7 762 Prog Biochem Biophys 2012; 39 (8) peptide -induced hippocampal neuronal apoptosis Free Rad Biol Med, 2004, 36(2): [22] Wan L, Nie G J, Zhang J, et al β-amyloid peptide increases levels of iron content and oxidative stress in human cell and C elegans models of Alzheimer's disease Free Radical Biology and Medicine, 2011, 50(2): [23] Butterfield D A, Howard B, Yatin S, et al Elevated oxidative stress in models of normal brain aging and Alzheimer's disease Life Sci, 1999, 65(10): [24] Bains J S, Shaw C A Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death Brain Res Rev, 1997, 2(3): [25] Bush A I Metals and neuroscience Curr Opin Chem Biol, 2000, 4(2): [26] Sayre L M, Perry G, Harris P L R, et al In situ oxidative catalysis by neurofibrlllary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals J Neurochem, 2000, 74(2): [27] Lovell M A, Robertson J D, Teesdale W J, et al Copper, iron and zinc in Alzheimer's disease senile plaques J Neurol Sci, 1998, 158(31): [28] Zhang J, Mori A, Zhao B L Fermented papaya preparation attenuates APP: A<beta> mediated copper neurotoxicity in APP and APPsw overexpressing SH-SY5Y cells Neuroscience, 2006, 143(1): [29] Spires T L, Meyer-Luehmann M, Stern E A, et al Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy J Neurosci, 2005, 25(12): [30] Naumann N, Alpar A, Ueberham U, et al Transgenic expression of human wild-type amyloid precursor protein decreases neurogenesis in the adult hippocampus Hippocampus, 2010, 20(6): [31] Simon A M, Schiapparelli L, Salazar-Colocho P, et al Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Abeta levels Neurobiol Dis, 2009, 33(3): [32] Wan L, Nie G, Zhang J, et al Overexpression of human wild-type amyloid- protein precursor decreases the iron content and increases the oxidative stress of neuroblastoma SH-SY5Y cells J Alzheimer's Disease, 2012, 30(4): [33] Tenenbaum A, Malkiel S, Wexler I D, et al Anemia in Children with Down Syndrome International J Pediatrics, 2011: Article ID [34] Devi L, Prabhu B M, Galati D F, et al Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain: is associated with mitochondrial dysfunction J Neurosci, 2006, 26(35): [35] Duce J A, Tsatsanis A, Cater M A, et al Iron-export ferroxidase activity of -amyloid precursor protein is inhibited by zinc in Alzheimer's disease Cell, 2010, 142(8): [36] Dixon N E, Crissman B G, Smith P B, et al Prevalence of iron deficiency in children with down syndrome J Pediatrics, 2010, 157(9): [37] Rogers J T, Randall J D, Cahill C M, et al An iron-responsive element type in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript J Biol Chem, 2002, 277(13): [38] Cho H H, Cahill C M, Vanderburg C R, et al Selective translational control of the Alzheimer amyloid precursor protein transcript by iron regulatory protein-1 J Biol Chem, 2010, 285 (15): [39] Atamna H, Killilea D W, Killilea A N, et al Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging Proc Natl Acad Sci USA, 2002, 99(12): [40] Shah R C, Buchman A S, Wilson R S, et al Hemoglobin level in older persons and incident Alzheimer disease Neurology, 2011, 77(2): [41] Liu Q, Zhao B-L Nicotine attenuates β-amyloid peptide induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures Brit J Pharmocol, 2004, 141: [42] Zhang J, Liu Q, Liu N Q, et al Nicotine reduces β-amyloidosis by regulating metal homeostasis FASEB J, 2006, 20(10): [43] Liu Q, Zhang J, Qin C, et al Dissecting the signalling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model FASEB J, 2007, 21(1): [44] Zhao B L The prevention mechanisms of nicotine against Parkinson's disease and Alzheimer's disease Acta Biophysc Sinica, 2007, 23: [45] Zhao B L Smoking, free radicals and health Acta Biophysc Sinica, 2007, 28: [46] Pu Y M, Wang Q, Qian Z M Effect of iron and lipid peroxidation on development of cerebellar granule cells in vitro Neuroscience, 1999, 89(3): [47] Mandel S, Amit T, Bar-Am O, et al Iron dysregulation in Alzheimer's disease: Multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents Prog Neurobiol, 2007, 82(6): [48] Lovell M A, Robertson J D, Teesdale W J, et al Copper, iron and zinc in Alzheimer's disease senile plaques J Neurol Sci, 1998, 158(1): [49] Smith M A, Rottkamp C A, Nunomura A, et al Oxidative stress in Alzheimer's disease Biochim Biophys Acta, 2000, 1502 (2): [50] Barnham K J, Masters C L, Bush A l Neurodegenerative diseases and oxidative stress Nat Rev Drug Discov, 2004, 3(2): [51] Nunomura A, Perry G, Pappolla M A, et al RNA oxidation is a prominent feasure of vulnerable neurons in Alzheimer's disease J Neurosci, 1999, 19: [52] I Bannon D, Portnoy M E, Olivi L, et al Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells Biochem Biophys Res Commun, 2002, 295(4):

8 2012; 39 (8), 763 [53] Hill J M The distribution of iron in the brain In: Youdium MBH ed Brain iron: neurochemical and behavioral aspects London, New York and Philadelphia: Taylor and Francis2, 1988 [54] Beard J L, Connor J R, Jones B C Iron in the brain Nutr Rev, 1993, 51: [55] Zheng W, Xin N, Chi Z H, et al Divalent metal transporter 1 is involved in amyloid precursor protein processing and A generation FASEB J, 2009, 23(13): [56] Wu Z F, Zhang J, Zhao B L Superoxide anion regulates the mitochondrial free Ca 2+ through uncoupling proteins Antioxid Redox Signal, 2009, 11(12): [57] Luo Y, Zhang J, Liu N, et al Copper ions influence the toxicity of beta-amyloid (1-42) in a concentration-dependent manner in a Caenorhabditis elegans model of Alzheimer's disease Sci China Life Sci, 2011, 54(5): [58] Reif D W, Simmons R D Nitric oxide mediates iron release from ferritin Arch Biochem Biophys, 1990, 283(5): [59] Li Y, Pan W, Song T Magnetite mechanisms in Alzheimer's disease Acta Biophysica Sinica, 2011, 27(2): [60] Cabrejo L, Guyant-Marechal L, Laquerriere A, et al Phenotype associated with APP duplication in five families Brain, 2006, 129(15): [61] Rovelet-Lecrux A, Hannequin D, Raux G, et al APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy Nat Genet, 2006, 38(1): [62] Saganich M J, Schroeder B E, Galvan V, et al Deficits in synaptic transmission and learning in amyloid precursor protein (APP) transgenic mice require C-terminal cleavage of APP J Neurosci, 2006, 26(13): Metal Metabolic Homeostasis Disruption and Early Initiation of Mechanism for Alzheimer s Disease * ZHAO Bao-Lu **, WAN Li (State Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing , China) Abstract Many studies have shown there is a close relationship between metal homeostasis disruption and Alzheimer's disease (AD), but the mechanism needs to be discussed Recent progresses about these studies are reviewed especially the results in author's laboratory are discussed Iron and copper homeostasis disruption, oxidative stress β-amyloid (Aβ), amyloid precursor protein (APP), iron regulatory protein (IRP) and divalent metal transporter 1(DMT1) are discussed in detail We suggested that the overload of iron and copper might have closer relationship with the oxidative stress damage in the later phase in AD and the deficiency of iron and copper might have closer relationship with the early initiation of AD The protective effects of natural antioxidant against AD through regulating iron and copper homeostasis disruption and oxidative stress are also discussed This review may be useful for further research and prevention and therapy of AD Key words Alzheimer's disease (AD), metal iron homeostasis disruption, oxidative stress, β-amyloid (Aβ), amyloid precursor protein (APP), iron regulatory protein (IRP), divalent metal transporter 1 (DMT1), natural antioxidants DOI: /SPJ * This work was supported by a grant from The National Natural Science Foundation of China( , ) **Corresponding author Tel: , zhaobl@sun5ibpaccn Received: June 14, 2012 Accepted: June 29, 2012

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