, AD amyloid precursor protein,app) ( < 100 mg) , ( mg) CURE CREDO ,, TTP, ; : R : A : (2005) A

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1 22 Foreign Medical Sciences Section on Pharmacy 2005 Feb ; 32(1) ( < 100 mg) ( mg) CURE CREDO TTP ( / ) : (AD) (A ) A AD A 2 2 AD 2 A : ; ; ; : R : A : (2005) A A (Alzheimer s disease AD) A ( 2 AD amyloid precursor protein APP) AD 2 2 (secretase) APP 2 ( neurofibrillary tangle NFT) ( senile A N plaque) NFT tau APP (soluble APP2sAPP2 ) C (C2terminal fragment CTF) CTF2 (amyloid 2protein A ) A(3943 ) CTF2 AD AA 40 A 42 A 40 A 42 A 42 4 ku A 40 A A A APP AD 2 A APP NFT A sapp2 : (1)

2005 2 32 1 23 : 2 ; ϖ : 2 ; : 2 ;APP : ;CTF :C ;sapp : APP A 2 A (NASID) AD 2 2.

2 : 2 ; ϖ : 2 ; : 2 ;APP : ;CTF :C ;sapp : APP A 2 A (NASID) AD APP APP 2 APP A N 2 A : A : (1) 2 AD AD ; (2) 2 A APP ( APP E ) ; (3) A ( ) 2 A ; (4) 2 APP A 1999 APP Lambert A A ( beta2site amyloid precursor protein cleavage en2 (A 2derived diffusible ligands ADDL zyme BACE)21 2 A ) (protofibrils) asp2 memapsin22 [1 ] A AD BACE21 55 % BACE22BACE21 A BACE22 ( aspartyl proteases) : (DTGS) (DSGT) D93 D AD 2 (pepsin) A BACE BACE21 BACE Fluhrer BACE21 A 2 (a disintegrin and metal2 : (1) BACE21 mrna loproteases ADAM) BACE22 ; (2) BACE21 A [2 3 (zinc metalloproteinase) ] ; (3) BACE22 2 APP BACE21 2 APP 2 ; ( 4) BACE21 2 [4 adamalysin BACE22 ] BACE21 (tumor necrosis factor2alpha convertase TACE : BACE21 ADAM17) ADAM9 ADAM10 2 AD(early onset AD) Cruts [5 ] C(PKC) 11 BACE21 sapp2 PKC AD Fluhrer [4 ] 2 BACE21 A

3 24 Foreign Medical Sciences Section on Pharmacy 2005 Feb ; 32(1) 11 AN (Asp32 Asp228) 2003 Hook [8 ] 2 [6 ] AD A BACE22 A 1 APP 2 2 A Fluhrer [4 ] (neuronal chromaffin cells) BACE22 A 2 APP 1920 BACE22 (cysteine proteases) 2 (Flemish) 2 BACE21 AD(familial Alzheimer s disease FAD) ( < 5 %) A 21 2 (wild2type) BACE22 2 A AD BACE21 BACE22 FAD 21 (Swedish) FAD BACE22 Down AD BACE22 2 A Down BACE21 BACE21 APP A A AD BACE21 AD BACE A (prese2 CTF2 2 nilin PS) 1 - / - BACE21 A BACE21 A BACE21 A PS FAD PS APP Kitazume A A [7 ] BACE21 : PS 2 (sialyltransferase) ST6Gal PS1/ PS2 2 BACE21 BACE22 PS 2 PS BACE22 A 6 7 APP mrna N C APP 2 1 nmol L - 1 PS BACE21 N C 2 PS 2 PS APP 2 (statine) P1 A APP CTF IC PS mol L - 1 OM9921 OM9922 Statv PS 7 SIB1281 SIB IC mol L - 1 X C 2

4 E2 JLK PS Nicastrin aph21 pen22 2 [9 2 ] NASID A Takasugi [10 ] S2 (Schneider cells) Notch PS 2 aph21 Nicastrin PS 3 (holoprotein) pen22 PS ku ku PS Nicas2 trin aph21 pen22 2 AD A A 20 %30 % AD 2 APP A C A; NICD( noch intracellular [15 ] 2 AD domain) AICD (intracellular domain of APP) Iwat2 subo [11 ] : (1) 2? (2) FAD PS1 PS2 A 42 [1 ] Lashuel HA Hartley D Petre BM et al. Neurodegenera2? 2 tive disease : amyloid pores from pathogenic mutations[j ]. APP 2 Nature (6895) :291. [2 ] Luo Y Bolon B Kahn S et al. Mice deficient in BACE1 Notch ErbB4 the Alzheimer s beta2secretase have normal phenotype and E2 2 abolished beta2amyloid generation[j ]. Nat Neurosci 2001 Notch S3 4 (3) : Notch PS 2 [3 ] Roberds SL Anderson J Basi G Dovey [12 ] et al. BACE knockout APP mice are healthy despite lacking the primary beta2secretase 2 activity in brain : implications for Alzheimer s disease thera2 A peutics[j ]. Hum Mol Genet (12) : [4 ] Fluhrer R Capell A Westmeyer G et al. A non2amy2 2 loidogenic function of BACE22 in the secretory pathway[j ]. Notch ErbB4 J Neurochem (5) : Notch ErbB4 [5 ] Cruts M Dermaut B Rademakers R et al. Amyloid beta secretase gene (BACE) is neither mutated in nor associated with early2onset Alzheimer s disease [ J ]. Neurosci Lett (1/ 2) : Petit [13 ] [6 ] Huse JT Liu K Pijak DS et al. Beta2secretase processing 2 in the trans2golgi network preferentially generates truncated Notch A amyloid species that accumulate in Alzheimer s disease brain 2003 Petit [14 ] [J ]. J Biol Chem (18) : JLK ( [7 ] Kitazume S Tachida Y Oka R et al. Alzheimer s beta2 ) A secretase beta2site amyloid precursor protein2cleaving en2 Notch JLK zyme is responsible for cleavage secretion of a Golgi2resi2

5 26 Foreign Medical Sciences Section on Pharmacy 2005 Feb ; 32(1) dent sialyltransferase[j ]. Proc Natl Acad Sci USA (24) : [8 ] Hook VY Reisine TD. Cysteine proteases are the major 2 secretase in the regulated secretory pathway that provides most of the 2amyloid in Alzheimer s disease : role of BACE2 1 in the constitutive secretory pathway[j ]. J Neurosci Res (3) : [9 ] Van Gassen G Annaert W. Amyloid presenilins and Alzheimer s disease[j ]. Neuroscientist (2) : [10 ] Takasugi N Tomita T Hayashi I et al. The role of prese2 nilin cofactors in the 2secretase complex [ J ]. Nature (6930) : [11 ] Iwatsubo T. The 2secretase complex : machinery for intra2 membrane proteolysis [ J ]. Curr Opin Neurobiol (3) : [12 ] Dovey HF John V Anderson JP et al. Functional gam2 ma2secretase inhibitors reduce beta2amyloid peptide levels in brain[j ]. J Neurochem (1) : [13 ] Petit A Bihel F Alves da Costa C et al. New protease inhibitors prevent gamma2secretase2mediated production of Abeta40/ 42 without affecting Notch cleavage [J ]. Biol (5) : Nat Cell [14 ] Petit A Pasini A Alves da Costa C et al. JLK isocoumar in inhibitors : selective 2secretase inhibitors that do not in2 terfere with notch pathway in vitro or in vivo[j ]. J Neurosci Res (3) : [15 ] Weggen S Eriksen JL Das P et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxyge2 nase activity[j ]. Nature (6860) : ( ) : Medline : ; ; ; : R : A : (2005) Bettie 5 20 : (amisulpride) (aripiprazole) (clozapine) (olanzapine) (que2 tiapine) (risperidone) (ziprasidone) (zotepine) Thonnard2Neumann :

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