ライフサイエンスコーパス: alpha-secretase

1 , thus leading to loss-of-function of ADAM17 alpha-secretase.

2 alpha-converting enzyme, a primary candidate alpha-secretase.

3 avage of APP but not alternative cleavage by alpha-secretase.

4 sphorylated on T668 verses those produced by alpha-secretase.

5 ubstrates which would normally be cleaved by alpha-secretase.

6 n-amyloidogenic processing of beta-APP751 by alpha-secretase.

7 amyloidogenic cleavage of APP as the primary alpha-secretase.

8 APP is also cleaved by alpha-secretase.

9 rons and identified which protease acts as a alpha-secretase.

10 dothelin-converting enzyme-1, neprilysin and alpha-secretase.

11 lloprotease which is thought to be the major alpha-secretase.

12 strategy based on promoting APP cleavage by alpha-secretases.

13 proteinase-10 (ADAM-10) and ADAM-17, two APP alpha-secretases.

14 ell surface, and increases their cleavage by alpha-secretases.

15 passing the beta-amyloid domain (betaA), the alpha-secretase 11-12 kDa intermediate, ApoE and tau.

16 ated fibrinolysis.SIGNIFICANCE STATEMENT The alpha-secretase a-disintegrin and metalloproteinase (ADA

17 Conversely, the alpha-secretase "a disintegrin and metalloproteinase" 10

18 Regulated and unregulated alpha-secretase activities have been reported, and the f

19 cleavage events are associated with elevated alpha-secretase activity and enhanced hydrolysis of tumo

20 an excitotoxic stimulus (i.e. NMDA) inhibits alpha-secretase activity and markedly diminishes soluble

21 Alpha-secretase activity and secreted APPalpha generatio

22 Our results also suggest that increasing alpha-secretase activity as a therapeutic route must be

23 umor necrosis factor-alpha-converting enzyme alpha-secretase activity but had no effect on beta-site

24 Inhibition of alpha-secretase activity by TAPI-1 treatment blocked LAR

25 alpha-Secretase activity did not increase significantly.

26 In yeast, alpha-secretase activity has been attributed to glycosyl

27 d in decreased ROCK1 expression and elevated alpha-secretase activity in vivo.

28 Secretion of soluble betaAPP via alpha-secretase activity increased significantly in cell

29 ted SIRT1-mediated response, suggesting that alpha-secretase activity is required for SIRT1-mediated

30 lly, both mutations significantly attenuated alpha-secretase activity of ADAM10 (>70% decrease), and

31 In Tg2576 AD mice, both mutations attenuated alpha-secretase activity of ADAM10 and shifted APP proce

32 nstrating that inhibition of ADAM9 increases alpha-secretase activity on the cell membrane.

33 been reported, and the fraction of cellular alpha-secretase activity regulated by protein kinase C (

34 The protease is tightly linked with alpha-secretase activity toward the amyloid precursor pr

35 After addition of TACE (which has alpha-secretase activity) to mitotically arrested adult

36 ng of amyloid precursor protein by enhancing alpha-secretase activity, a key regulatory step in the e

37 recombinant antibody fragments for potential alpha-secretase activity, a naturally occurring enzyme t

38 ng prodomain chaperone function, attenuating alpha-secretase activity, and reducing adult hippocampal

39 vely, these findings suggest that diminished alpha-secretase activity, owing to LOAD ADAM10 prodomain

40 PKC activation enhances alpha-secretase activity, which results in a decrease of

41 ociated with promotion of anti-amyloidogenic alpha-secretase activity.

42 ter (Z-lys-o-Np) as a preliminary screen for alpha-secretase activity.

43 tor Ro31-9790, which indicated mediation via alpha-secretase activity.

44 ma-secretase activities as well as inducible alpha-secretase activity.

45 oblasts, a dual dysregulation of APP and the alpha-secretase ADAM10 leads to the production of an exc

46 h batimastat or GI254023X, inhibitors of the alpha-secretase ADAM10, prevented sAPPalpha generation a

47 nes the abundance and association of APP and alpha-secretases ADAM10 (a disintegrin and metalloprotei

48 s the expression of AD-relevant genes: BDNF, alpha-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1

49 s the transcription of the gene encoding the alpha-secretase, ADAM10.

50 lude that under CH the level of the putative alpha-secretases, ADAM10 and TACE are regulated by post-

51 fragment that results from APP processing by alpha-secretase, an as yet unidentified enzyme that clea

52 Adam9 and Psen1 mRNA, which code for a minor alpha-secretase and gamma-secretase, respectively, were

53 dergo sequential cleavage mediated by either alpha-secretase and PS/gamma-secretase or BACE1 and PS/g

54 1 is known to undergo ectodomain shedding by alpha-secretase and subsequent proteolytic processing by

55 T-I/II can block the proteolytic activity of alpha-secretase and the activation of PKC and Rho in res

56 sequentially cleaved by ectodomain-shedding alpha-secretases and the gamma-secretase complex, a proc

57 main of APP is required for association with alpha-secretases and, as analyzed by Western blot, for a

58 oid precursor protein secretion (alphaAPPs), alpha-secretase, and PKCalpha expression but had no effe

59 We also found that p75NTR, alpha-secretases, and the four subunits of the gamma-sec

60 ctivity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons

61 By detecting regulated alpha-secretase APP cleavage in the TGN by TACE/ADAM-10,

62 ellularly, and we also showed that regulated alpha-secretase APP cleavage occurs in the TGN using an

63 tify the intracellular site of PKC-regulated alpha-secretase APP cleavage.

64 r, the physical interactions between APP and alpha-secretases are not well understood.

65 eurons and shifted APP processing toward the alpha-secretase, as determined by augmented soluble APPa

66 Alternative cleavage of the APP by alpha-secretase at A beta 16/17 generates the C-terminal

67 Alternative cleavage of the APP by alpha-secretase at Abeta16/17 releases the secreted deri

68 e report that APP is processed by endogenous alpha-secretase at the trans-Golgi network (TGN) of both

69 d from the plasma membrane after cleavage by alpha-secretase, but not by beta-secretase.

70 etase but not A10, suggesting that beta- and alpha-secretases can form distinct complexes with gamma-

71 isintegrin and metalloprotease family, is an alpha-secretase capable of anti-amyloidogenic proteolysi

72 te that expression of the KPI domain reduces alpha secretase cleavage so that less P3 and relatively

73 -bound C-terminal fragments of APP from both alpha-secretase cleavage (alpha-CTF, named C83 according

74 icial effects were associated with increased alpha-secretase cleavage activity, but no significant al

75 ADAM9 or -17) is critical for EGCG-mediated alpha-secretase cleavage activity.

76 PP and ApoER2 away from the cell surface and alpha-secretase cleavage and encourages endocytosis and

77 Moreover, alpha-secretase cleavage can potentiate the inhibitory e

78 PKC-regulated APP alpha-secretase cleavage has been shown to involve tumor

79 Little is known about the role of alpha-secretase cleavage in gamma-secretase regulation.

80 ase in both A beta and APPs alpha given that alpha-secretase cleavage of a single APP molecule preclu

81 We found that TIMP-3 inhibited alpha-secretase cleavage of APP and an apolipoprotein E

82 nteractome of ISVAID suggests that beta- and alpha-secretase cleavage of APP cuts inside the interact

83 Although unregulated alpha-secretase cleavage of APP has been shown to occur

84 and support the generally held concept that alpha-secretase cleavage of APP occurs at the cell surfa

85 tatins is largely mediated by stimulation of alpha-secretase cleavage of APP, resulting in increased

86 The presence of sortilin promotes alpha-secretase cleavage of APP, unlike SorLA, which inh

87 eceptors and catalyzes the non-amyloidogenic alpha-secretase cleavage of the Alzheimer's precursor pr

88 r in platelet secretion products as sAPP, an alpha-secretase cleavage product of the beta-amyloid pre

89 f APP and increased secretion of the soluble alpha-secretase cleavage product sAPPalpha.

90 The alpha-secretase cleavage products of APP were increased

91 D) within alphaCTF, which is bisected by the alpha-secretase cleavage site, contributes to this negat

92 hed fluorogenic APP peptide substrate at the alpha-secretase cleavage site.

93 rmined that 1) cholesterol binds to Abeta at alpha-secretase cleavage site; 2) Abeta17-40 rather than

94 ISVAID contains the beta- and alpha-secretase cleavage sites of APP: proteomic analysi

95 ociated helix located just after the site of alpha-secretase cleavage that helps to organize the conn

96 The initial alpha-secretase cleavage was extracellular to the transm

97 in Alzheimer's disease (AD), is precluded by alpha-secretase cleavage within the Abeta domain of the

98 PrP(c)) undergo similar disintegrin-mediated alpha-secretase cleavage yielding N-terminal secreted pr

99 ary for EGCG promotion of non-amyloidogenic (alpha-secretase cleavage) APP processing.

100 (the soluble N-terminal derivative following alpha-secretase cleavage) were precipitated from lysates

101 ated form of Abeta, known as "p3," formed by alpha-secretase cleavage, did not exhibit a rise.

102 se cleavage was immediate and did not affect alpha-secretase cleavage.

103 uble APP fragment (sAPPalpha) released after alpha-secretase cleavage.

104 ough a high level of Abeta can be toxic, the alpha-secretase cleaved APP (sAPPalpha) is neuroprotecti

105 cells secrete high levels of sAPPalpha, the alpha-secretase cleaved ectodomain fragment of APP, as c

106 Here, we show that alpha-secretase-cleaved APP C-terminal product (alphaCTF

107 s and increased secretion of neuroprotective alpha-secretase-cleaved APP fragments.

108 In contrast, alpha-secretase cleaves APP within the Abeta sequence an

109 tein-coupled receptors are known to activate alpha-secretase-dependent processing of APP; however, th

110 reviously reported to increase the levels of alpha-secretase-derived APP (APPs alpha).

111 and reduce production of the neuroprotective alpha-secretase-derived form of APP (sAPPalpha).

112 homology to soluble aspartyl proteases, and alpha-secretase displays characteristics of certain memb

113 oward the non-amyloidogenic pathway, because alpha-secretase enzymatic activity was increased in the

114 bol-13-acetate treatment or expression of an alpha-secretase enzyme, ADAM10, resulted in ectodomain c

115 evaluated the involvement of three candidate alpha-secretase enzymes, a-disintegrin and metalloprotea

116 factor-like growth factor (HB-EGF) and as an alpha secretase for the amyloid precursor protein.

117 inducing the release of the nonamyloidogenic alpha-secretase form of soluble APP (sAPPalpha) into the

118 ction and activity through activation of the alpha-secretase gene ADAM10.

119 ed a concomitant diminution in the levels of alpha-secretase-generated soluble APP derivatives (APP s

120 e also detected age-dependent increase in an alpha-secretase in ASD brains.

121 This work reveals an unforeseen role for alpha-secretase in generating an endogenous gamma-secret

122 gainst an essential major role of MDC9 as an alpha-secretase in mice.

123 only a moderate and transient activation of alpha-secretase in neuronal cells.

124 id precursor protein (APP) can be cleaved by alpha-secretases in neural cells to produce the soluble

125 SCNA (alpha-synuclein) and ADAM10 (alpha-secretase) increased (both ANOVA, P<0.02) but PSEN

126 alpha-Secretase initiates the non-amyloidogenic pathway

127 ADAM10 (A10), the principal neuronal alpha-secretase, interacted and cofractionated with gamm

128 oluble APPalpha (sAPPalpha) generated by the alpha-secretase is known to stimulate dendritic branchin

129 Because alpha-secretase is the enzyme responsible for the non-am

130 essed the impact on memory of the Drosophila alpha-secretase kuzbanian (KUZ), the enzyme initiating t

131 proteolytic activity against Abeta, one with alpha-secretase-like activity and one with carboxypeptid

132 light chain antibody fragment, c23.5, showed alpha-secretase-like activity, producing the 1-16 and 17

133 f Abeta40 with c23.5, the light chain having alpha-secretase-like cleavage, substantially increases t

134 se-type cleavage, suggesting that yeast have alpha-secretase-like protease(s).

135 gest that cleavage of APP by either beta- or alpha-secretase may inactivate the ISVAID, thereby enhan

136 ma membrane is considered the major site for alpha-secretase-mediated APP cleavage, but other cellula

137 specifically reduce beta-secretase- but not alpha-secretase-mediated cleavage of endogenous APP in c

138 undergo a series of prohormone convertase or alpha-secretase-mediated cleavages before the remaining

139 creasing meprin beta-mediated and decreasing alpha-secretase-mediated processing of APP at the plasma

140 and caveolins may play a pivotal role in the alpha-secretase-mediated proteolysis of APP in vivo.

141 actor superfamily of receptors, undergoes an alpha-secretase-mediated release of its extracellular do

142 These events are initiated by an alpha-secretase-mediated release of the extracellular do

143 discovery of a novel endogenous modulator of alpha-secretase-mediated, in preference to beta-secretas

144 odels, whereas Lahiri and Sokol have studied alpha-secretase (non-amyloidogenic or anabolic) processi

145 nd-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precu

146 soluble APP (sAPPalpha) derived by action of alpha-secretase on APP, coinciding with a decrease in pr

147 Elevated alpha-secretase or BACE1 activities increased C-terminal

148 main contains the sites cleaved by beta- and alpha-secretases: our data suggest that beta-/alpha clea

149 low cellular cholesterol levels favored the alpha-secretase pathway and decreased A beta secretion p

150 a APP is sorted into either the constitutive alpha-secretase pathway or the amyloidogenic beta-secret

151 The interaction of the beta-secretase and alpha-secretase pathway-mediated processing of APP in th

152 APP shunting from the beta-secretase to the alpha-secretase pathway.

153 it Abeta secretion through activation of the alpha-secretase pathway.

154 mer disease (AD), whereas cleavage of APP by alpha-secretases precludes Abeta formation.

155 a), or along the nonamyloidogenic pathway by alpha-secretase, precluding Abeta production.

156 Cleavage of APP by alpha-secretase prevents Abeta formation, producing nona

157 Cleavage of APP by alpha-secretase prevents Abeta formation, producing nona

158 secretase inhibitors significantly increased alpha-secretase processing (r = -0.86) and decreased bet

159 indings identify the TGN as a major site for alpha-secretase processing in HeLa cells and primary neu

160 mes higher than that of C99, indicating that alpha-secretase processing is the major pathway and that

161 e in the inhibition of the non-amyloidogenic alpha-secretase processing of the amyloid precursor prot

162 Importantly, alpha-secretase processing was significantly promoted by

163 on of endogenous APP in the TGN and enhanced alpha-secretase processing.

164 onal significance of the ISVAID and of beta-/alpha-secretase-processing of APP using various ISVAID-d

165 , peptides representing the product of beta-/alpha-secretase-processing of ISVAID did not alter excit

166 ic agonists stimulates the nonamyloidogenic, alpha-secretase-processing pathway of amyloid precursor

167 In contrast to the marked activation of alpha-secretase produced by PKC activators in fibroblast

168 Alternative betaAPP cleavage by alpha secretase produces a slightly longer NH2-terminal

169 APP cleavage by alpha-secretase produces potentially neurotrophic secret

170 s dramatically enhances the secretion of the alpha-secretase product sAPP alpha in fibroblasts from A

171 Mechanistically, SIRT1 increases alpha-secretase production and activity through activati

172 is process was enhanced by the inhibition of alpha-secretase proteolysis and by co-expression with th

173 lating neuronal ADAM10 expression and, thus, alpha-secretase proteolysis of APP.

174 aques via promotion of the non-amyloidogenic alpha-secretase proteolytic pathway in "Swedish" mutant

175 iated with promotion of the nonamyloidogenic alpha-secretase proteolytic pathway.

176 e-612 to valine (K612V), intended to abolish alpha-secretase recognition and to preserve the A beta d

177 the beta-amyloid precursor protein (APP) by alpha-secretase releases a secreted form of APP (sAPP) f

178 be cleaved within the amyloid beta domain by alpha-secretase releasing the non-amyloidogenic product

179 Our data suggest that TACE may be the alpha-secretase responsible for the majority of regulate

180 n and metalloproteinase 10) is the principal alpha-secretase responsible for the non-amyloidogenic pr

181 rompted us to hypothesize that PKC-regulated alpha-secretase(s) also reside in this organelle.

182 d the large secreted derivatives produced by alpha secretase (sAPPalpha) and beta secretase (sAPPbeta

183 and C-terminal fragments of APP generated by alpha-secretase (sAPPalpha) (C83) versus beta-secretase

184 their respective mRNA levels and reduced the alpha-secretase shedding of APP by 60% and 30%, respecti

185 yloidogenic cleavage of APP, upregulation of alpha-secretase shifts APP processing to reduce the path

186 APP occurred at His(14)/Gln(15), not at the alpha-secretase site and was inefficient (k(cat)/K(m) (1

187 c nanobody engineered to cleave Abeta at its alpha-secretase site has potential therapeutic value.

188 r, V(max)/K(m) for a substrate mimicking the alpha-secretase site in human beta amyloid precursor pro

189 ovary (CHO) cell line by cleaving APP at the alpha-secretase site which precludes formation of Abeta.

190 ces at the beta-secretase site, and near the alpha-secretase site, mainly at A beta-Phe(20)--Ala(21)

191 t efficiently cleaves the sequences near the alpha-secretase site.

192 We utilized the synthetic alpha-secretase substrate, benzyloxycarbonyl-l-lysine o-

193 he expression of ADAM10 and another putative alpha-secretase, TACE, as well as the beta-secretase, BA

194 However, APP can also be cleaved by an alpha-secretase to form a non-amyloidogenic secreted for

195 APP is cleaved by beta- and alpha-secretase to produce APP-C99 and APP-C83, which ar

196 can be cleaved by beta-secretase (BACE) and alpha-secretase to produce APP-C99 and APP-C83.

197 hese results establish a molecular basis for alpha-secretase-type cleavage in yeast and support the g

198 ectively termed yapsin), are responsible for alpha-secretase-type cleavage of APP expressed in yeast,

199 rotein (APP) introduced into yeast undergoes alpha-secretase-type cleavage, suggesting that yeast hav

200 Up-regulation of alpha-secretase, which can hydrolyze Abeta between Lys16

201 abolism in cell culture involves cleavage by alpha-secretase, which cleaves within the Abeta sequence