Reviews and Monographs

Reviews and Monographs Progress in Biochemistry and Biophysics 2012, 39(8): 756~763 wwwpibbaccn (AD), AD, AD,, AD AD * ** ( 100101) (AD) β- β- AD AD β- (Aβ) β- R74 DOI: 103724/SPJ1206201200297 (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 * (30930036, 30870587) ** Tel: 010-64888569, E-mail: zhaobl@sun5ibpaccn (ROS) (RNS) 2012-06-14 2012-06-29

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) 21 21 ( ) Cu + Fe 2+ 21 ( APP

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

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+

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)

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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: 157 170 [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): 4207 4217 [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): 1805 1818 [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): 527 534 [58] Reif D W, Simmons R D Nitric oxide mediates iron release from ferritin Arch Biochem Biophys, 1990, 283(5): 537 541 [59] Li Y, Pan W, Song T Magnetite mechanisms in Alzheimer's disease Acta Biophysica Sinica, 2011, 27(2): 121 126 [60] Cabrejo L, Guyant-Marechal L, Laquerriere A, et al Phenotype associated with APP duplication in five families Brain, 2006, 129(15): 2966 2976 [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): 24 26 [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): 13428 13436 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 100101, 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: 103724/SPJ1206201200297 * This work was supported by a grant from The National Natural Science Foundation of China(30930036, 30870587) **Corresponding author Tel: 86-10-64888569, E-mail: zhaobl@sun5ibpaccn Received: June 14, 2012 Accepted: June 29, 2012