Ion Channel Hypothesis for Molecular Mechanism of Alzheimer s Disease

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1 PROGRESS IN CHEMISTRY Vol. 18 No. 9 Sep ( ) A A A A A : Q26 : A : X(2006) Ion Channel Hypothesis for Molecular Mechanism of Alzheimer s Disease Zhang Chaofeng Du Huizhi Yang Pin 3 3 ( Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education Institute of Molecular Science Shanxi University Taiyuan China) Abstract Although many evidences point to Apeptides as playing a key role in pathogenesis of Alzheimer s disease (AD) no toxic mechanism has yet been demonstrated. The channel hypothesis of AD proposes that the A peptides which accumulate in plaques in the brain actually damage or kill neurons by forming ion channels. The ability of Apeptides to form these Achannels and the disruption of calcium homeostasis due to their formation could be the molecular mechanism of the neurotoxicity of A. The evidence for the channel hypothesis of Aneurotoxicity are reviewed and the emphasis is on the center role of Cu 2 + and Zn 2 + in AD. Key words Alzheimer s disease ; Apeptides ; ion channels ; calcium homeostasis ; Cu 2 + ; Zn 2 + (Alzheimer s disease AD) A AD ( senile dementia) Alosis Alzheimer 1907 AD A (senile plaque SP) [6 ] A ( neurofibrillary tangle NFT) % % 85 1 A % [1 ] A (amyloid precursor ( protein APP) APP amyloid protein A ) AD 3 [2 5 ] A SP APP : A : : (No ) 3 3 e2mail edu. cn

2 Lys 688Leu APP ; A 670Met 671Asp APP 670 A C AC A (1) A [7 ] 1 (APP) (A ) [7 ] Fig. 1 amyloid precursor protein and the formation of A [7 ] Fig. 2 2amyloid protein channel hypothesis [8 ] 2 molπl) [17 ] Cu 2 + A A APP A (1 40) A(1 42) molπl (2a) [8 ] molπl [20 ] NMR Raman EPRCD Zn 2 + Cu 2 + A Raman ph A N Arg 5 Lys 16 Lys 28 Zn 2 + Cu 2 + His(N )2metal2His(N ) [21 A 2 ] (3a) A Zn 2 + A ph Cu 2 + A A ph ph ( ) [9 ] A Cu 2 + His ( N) ; ph AD (714) Cu 2 + N His A Al 3 + (N ) (3b) Zn 2 + Cu 2 + Fe 3 + [10 12 ] Zn Cu Fe ph Zn 2 + Cu 2 + A AD [21 ] Zn Cu AD [13 14 AD ] [12 ] 1990 Zn Cu [15 18 ] A [22 ] Zn Cu [19 ] mol Zn 2 + [15 A 18 ] Zn 2 + A AD Zn Cu (1 40) ( K D = 107 nmolπl ) ( K D = 512 Zn 2 + Cu 2 + A (2b) [8 ] 2 A

3 A : (a) Zn 2 + Cu 2 + A ; (b) Cu 2 + [31 A ] hnt [32 ] [21 ] Fig. 3 Metal binding model of A: ( a ) A model for the insoluble aggregates of Zn 2 + 2and Cu 2 + 2A; (B) A model for the soluble Cu 2 + 2Acomplex at neutral ph [21 ] [6 ] 1 Table 1 Properties of channels formed by amyloid peptides [6 ] A (2c) 3 A [23 Arispe ] A(1 40) Ca 2 + [24 25 AD ] A(1 40) Al 3 + [23 ] Zn 2 + [26 ] Zn 2 + (2) Zn AD [12 ] : Zn 2 + ( mmolπl) A [27 28 ] ; (molπl) Zn 2 + [29 30 A ] A [25 ] [33 ] A(1 40) A(1 42) Ca 2 + A [34 35 ] A voltage2dependence single channel conductance ion selectivity blockade inhibition (ps) (permeability ratio) by zinc by Congo red A25 35 dependent cation( P K ΠP Cl = 1. 6) + + A 1 40 independent cation( P K ΠP Cl = 1. 8) + N. D. A1 40 independent cation( P K ΠP Cl = 11. 1) + N. D. A1 42 independent cation( P K ΠP Cl = 1. 8) + + islet amyloid polypeptide dependent 7. 5 cation( P K ΠP Cl = 1. 9) + + Prp independent cation( P K ΠP Cl = 2. 5) + + Prp independent various cation(variable) N. D. N. D. serum amyloid independent cation( P K ΠP Cl = 2. 9) + + CT105 independent 120 cation + + C-type peptide independent cation( P K ΠP Cl = 4. 6) micro-globulin independent non- selective + + transthyretin independent cation( P K ΠP Cl = 1. 6) + + Kawahara [36 ] A pS Zn 2 + (250molΠL) (1 40) GT127 A(1 40) GT127 A(1 40) (417molΠL) 3 30 min A(1 40) (1) [6 ]

4 Zn 2 + Ca Kim [37 ] AMBER Zn 2 + His14 N A(1 28) (4a) (4b) 4 A : (a) A(1 28) ; ( b) A (1 28) ; (c) A(25 35) 2 14 [37 ] Fig. 4 The energy2minimized Apeptide pore : (a) A(1 28) tetrameric aggregate ; ( b ) A( 1 28 ) pentameric aggregate ; (c) A(25 35) 2sheet aggregate [37 ] Zn 2 + A Zn ; Zn 2 + A ; Zn 2 + His13 (N )2Zn 2 + 2His14 (N ) A Zn 2 + A AD 5 (1) A [39 ] A (2) ; Ca 2 + Ca 2 + A [ Ca 2 + ] i [ Ca 2 + ] i [40 41 ] Fura22 AM A (1 40) [ Ca 2 + ] i [ Ca 2 + ] i A [ Ca 2 + ] i N 38! A [ Ca 2 + ] 4! ( ) 8! ( ) i A 5! 52 ps ( ) 311 ps ( A [ Ca 2 + ] i [ Ca 2 + ] i ) His6 Tyr9 A [42 ] [ Ca 2 + ] i 6 Ca 2 + A ATP (25 35) 14 (4c) [37 ] 34! [ Ca 2 + ] i 4 5! 131 ps APP APP A [43 2 ] A (3) A [38 ] (Fe 3 + Cu 2 + ) Fenton H 2 O 2 Zn 2 + A(10 21) OH (ROS) [20 ] APP A APP ; Cu 2 + Cu 2 + Fenton

5 [44 ] ROS O g- 2 H 2 O 2 OH NO : A Soto DNA [50 ] iab11 iab5 ; ; A A Cu 2 + Zn 2 + A (4) A AD [7 ] 6 N N N 2tetrakis ( 22pyridylmethyl) ethylenediamine ] [45 ] p K a Cu ( ) 2012 Zn Ca 2 + ( ) 1514 Ca ( ) 3 Mg 2 + ; BC [46 A ] (bathocuproine) p K a Zn ( ) 411 Cu ( ) [11 47 ] A 611 Mg 2 + Ca 2 + EGTA Fe 3 + Cu 2 + Fenton Zn 2 + Cu 2 + Zn 2 + Zn 2 + Mg 2 + Ca 2 + Al 3 + DFO A (desferrioxamine) Cu 2 + A A Fe 3 + Cu 2 + Zn 2 + [30 ROS ] Zn Cu [52 ] AD CQ(clioquinol) Zn A A [53 ] AD (3) A ( tacrine A A donepezilrivastigmine galantamine ) [7 ] ( vitamin Eselegiline ) AD ( risperidone olanzapine quetiapinziprasidone AD haloperidol) [48 ] A AD A A (1) A APP AD A A AD A AD Notch [49 ] (2) A Cu 2 + Zn 2 + Mg 2 + Ca 2 + AD A Cherny [51 ] Cu 2 + Zn 2 + : TPEN [ N [ 1 ] Holscher C. Neurobiol. Dis : [ 2 ] Chen Q S Kagan B L Hirakura Y et al. J. Neurosci. Res : [ 3 ] Cotman C W. Ann. N. Y. Acad. Sci : 1 16 [ 4 ] Cummings B J Pike C J Shankle R et al. Neurobiol. Aging : [ 5 ] Mattson M P. Physiol. Rev : [ 6 ] Kagan B L Hirakura Y Azimov R et al. Peptides :

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