ライフサイエンスコーパス: alpha-secretase

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

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

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

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

5 APP is also cleaved by alpha-secretase.

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

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

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

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

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

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

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

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

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

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

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

17 Alpha-secretase activity and secreted APPalpha generatio

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

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

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

21 alpha-Secretase activity did not increase significantly.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

48 1 is known to undergo ectodomain shedding by alpha-secretase and subsequent proteolytic processing by

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

78 The alpha-secretase cleavage products of APP were increased

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

141 Importantly, alpha-secretase processing was significantly promoted by

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

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

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

145 APP cleavage by alpha-secretase produces potentially neurotrophic secret

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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