ライフサイエンスコーパス: secretase

1 n (APP) by clipping enzymes (beta- and gamma-secretases).

2 of hair cells induced by inhibition of gamma-secretase.

3 beta-secretase 1 (BACE-1) followed by gamma-secretase.

4 affect the proteolytic activity of the gamma-secretase.

5 enilin 1 (PS1), a catalytic subunit of gamma-secretase.

6 sintegrin and metalloproteinase 10 and gamma-secretase.

7 ogical functional conformations of the gamma-secretase.

8 15), and its mRNA are regulated by PS1/gamma-secretase.

9 ncrease Abeta42 via complex effects on gamma-secretase.

10 tases can form distinct complexes with gamma-secretase.

11 resulting from proteolytic processing by eta-secretase.

12 ein (APP) by beta-secretase (BACE) and gamma-secretase.

13 site APP cleaving enzyme 1 (BACE1) and gamma-secretase.

14 re it is normally processed rapidly by gamma-secretase.

15 the substrate's ectodomain by alpha- or beta-secretases.

16 at are not further degraded by classical APP secretases.

17 ct with APP and modulate its cleavage by the secretases.

18 d precursor protein (APP) by beta- and gamma-secretases.

19 Egr-1 silencing also reduces levels of beta-secretase 1 (BACE-1) and BACE-1-cleaved amyloid precurso

20 e of amyloid precursor protein (APP) by beta-secretase 1 (BACE-1) followed by gamma-secretase.

21 dated small molecule inhibitors against beta-secretase 1 (BACE1), the assay was benchmarked with resp

22 ging to study a transmembrane protease, beta-secretase 1 (BACE1), whose ectoplasmic and cytoplasmic d

23 inhibitor, 4-fold more selective toward beta-secretase 1 in relation to beta-secretase 2 and 3-fold m

24 epend on clathrin-mediated endocytosis, beta-secretase 1, and interaction with clathrin adaptor prote

25 toward beta-secretase 1 in relation to beta-secretase 2 and 3-fold more resistant to in vitro metabo

26 the inhibition of the PS-1 isoform of gamma-secretase (33-fold vs PS-2), which may alleviate the adv

27 Conversely, the alpha-secretase "a disintegrin and metalloproteinase" 10 (ADAM

28 Delta-secretase, a lysosomal asparagine endopeptidase (AEP), s

29 n lipid raft fractions, with increased gamma-secretase accumulation upon CRF treatment.

30 PS1/gamma-secretase activates the transcription factor, cAMP respo

31 Here we show that the gamma-secretase activating protein (GSAP), a key enzyme in amy

32 a-secretase complex and its activator, gamma-secretase activating protein (GSAP).

33 d residual carboxy- and endo-peptidase gamma-secretase activities, similar to the formerly characteri

34 ocalization significantly influence its beta secretase activity and amyloid-beta (Abeta) production.

35 hermore, membralin deficiency enhances gamma-secretase activity and neuronal degeneration.

36 onstrated that RAGE function is dependent on secretase activity as ADAM10 and gamma-secretase inhibit

37 or X (Inh X), a compound that inhibits gamma-secretase activity before exposing to MAG or CNS myelin

38 under serum withdrawal, while blocking gamma-secretase activity had no effect.

39 mutation of the proposed pivot rescues gamma-secretase activity inNCT-deficient cells in a manner ind

40 reports, we and others have shown that gamma-secretase activity is enriched in mitochondria-associate

41 Modulation of gamma-secretase activity to reduce toxic amyloid-beta peptide

42 on, deposition in the ER, reduction of gamma-secretase activity, and impaired mitochondrial distribut

43 ation of PS1 at Ser367 does not affect gamma-secretase activity, but has a dramatic effect on Abeta l

44 cause loss of Presenilin function and gamma-secretase activity, including impaired Abeta production

45 e absence of presenilin expression and gamma-secretase activity, TNF-mediated JNK activation was prev

46 side of TMD4 affect Abeta42-generating gamma-secretase activity.

47 ract with BACE1 by negatively modulating its secretase activity.

48 that can be shown to directly modulate gamma-secretase activity.

49 teinases such as MT5-MMP, referred to as eta-secretase activity.

50 n1 mRNA expression, but both abolished gamma-secretase activity.

51 levels through indirect inhibition of gamma-secretase activity.

52 s, a dual dysregulation of APP and the alpha-secretase ADAM10 leads to the production of an excess of

53 a fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 1

54 expression of AD-relevant genes: BDNF, alpha-secretase (ADAM10), MINT2, FE65, REST, SIRT1, BIN1, and

55 Inhibition of gamma-secretase also decreases neuronal survival under GD cond

56 delta-secretase, also known as asparagine endopeptidase (AEP)

57 vel APP secretases (including delta- and eta-secretases, alternative beta-secretases) and additional

58 Westmark and colleagues have focused on beta-secretase (amyloidogenic) processing and the accumulatio

59 SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, le

60 rotein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity.

61 These observations implicate gamma-secretase and its mediated neurodevelopmental pathways i

62 Inhibition of gamma-secretase and metalloproteinase proteolysis in the NOTCH

63 Pharmacological inhibition of gamma-secretase and NOTCH1 processing also abrogates SKBR3 cel

64 ly link CRF to increased Abeta through gamma-secretase and provide mechanistic insight into how stres

65 platform enabling characterization of gamma-secretase and substrate within proteolipobead assemblies

66 can block the proteolytic activity of alpha-secretase and the activation of PKC and Rho in response

67 step for the subsequent processing by gamma-secretase and the release of gene regulatory intracellul

68 ntially cleaved by ectodomain-shedding alpha-secretases and the gamma-secretase complex, a process ca

69 delta- and eta-secretases, alternative beta-secretases) and additional metabolites, some of which ma

70 ar calcium, (2) activation of the BACE1 beta-secretase, and (3) ErbB4 receptor activation.

71 CTFs produced by eta-secretase are enriched in dystrophic neurites in an AD m

72 gamma-Secretases are a family of intramembrane-cleaving protea

73 (e.g. APP) are known to be involved in gamma-secretase assembly and in Abeta peptide production, resp

74 deletion has any significant impact on gamma-secretase assembly, activity, and stability, and that NC

75 not an essential element necessary for gamma-secretase assembly, activity, and stability, and that ro

76 lls, and then assessed their impact on gamma-secretase assembly, activity, and stability.

77 noprecipitation studies establish that gamma-secretase associates with CRFR1; this is mediated by bet

78 1-oriented stub is further cleaved by gamma-secretase at an -like site five amino acids N-terminal t

79 , it affects the cleavage precision of gamma-secretase at the gamma-site similar to certain Alzheimer

80 olved in the generation of Abeta is the beta-secretase BACE, for which powerful inhibitors have been

81 96) phosphorylation, and decreases both beta-secretase (BACE) and APOEepsilon4 gene expression.

82 the amyloid precursor protein (APP) by beta-secretase (BACE) and gamma-secretase.

83 ine templates for use in SAR studies of beta-secretase (BACE) inhibitors and also as versatile ligand

84 inhibition of the validated AD targets beta-secretase (BACE-1) and glycogen synthase kinase-3beta (G

85 c pocket of the aspartic acid protease, beta-secretase (BACE-1).

86 Inhibition of beta-secretase BACE1 is considered one of the most promising

87 A growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzhei

88 The beta-secretase (BACE1) initiates processing of the amyloid pr

89 Of relevance to Alzheimer's disease, beta-secretase (BACE1), the protein that initiates amyloidoge

90 The beta-secretase, BACE1 is a protease needed to generate active

91 ) is a major physiological substrate of beta-secretase (beta-site amyloid precursor protein-cleaving

92 genous BACE1 coimmunoprecipitated with gamma-secretase but not A10, suggesting that beta- and alpha-s

93 compound 11, that specifically blocks delta-secretase but not other related cysteine proteases.

94 est that the enzymatic function of PS1/gamma-secretase can be modulated by its 'phosphorylated' and '

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

96 amed JCasp- is naturally produced by a gamma-secretase/caspase double-cut of APP.

97 Herein, we demonstrate that gamma-secretase catalysis is driven by the stabilization of an

98 including presenilin (PS1 or PS2), the gamma-secretase catalytic core.

99 ess the frequency of susceptibility to gamma-secretase cleavage among human RTKs.

100 ewal upon proteolytic activation via a gamma-secretase cleavage complex (PS1, PS2) and TACE (ADAM17),

101 er protein that undergoes very similar gamma-secretase cleavage is the p75 neurotrophin receptor.

102 eta-Secretase cleavage occurs primarily at amino acids 504-5

103 t detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intracellula

104 rs and catalyzes the non-amyloidogenic alpha-secretase cleavage of the Alzheimer's precursor protein

105 ation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate Abeta,

106 ation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate amyloid

107 a-secretase substrate and suggest that gamma-secretase cleavage of TNFR1 represents a new layer of re

108 agment is a prerequisite for efficient gamma-secretase cleavage of TNFR1.

109 A detrimental APP mutation at the beta-secretase cleavage site linked to early-onset AD found i

110 eved to begin at or after the canonical beta-secretase cleavage site within the amyloid beta-protein

111 ecause this residue is just before the gamma-secretase cleavage site, we then investigated whether th

112 ydrogen bonds are at or near preferred gamma-secretase cleavage sites, suggesting that the sequence o

113 ecipient cells, and upon activation by gamma-secretase cleavage, induces NOTCH-specific gene expressi

114 family members AXL or TYRO3 depends on gamma-secretase cleavage.

115 sides the canonical alpha-, beta-, and gamma-secretases, cleave the amyloid precursor protein (APP) a

116 Additionally, CRFR1 and gamma-secretase co-localize in lipid raft fractions, with incr

117 oscopy showed that portions of A10 and gamma-secretase colocalize.

118 ), whose formation is regulated by the gamma-secretase complex and its activating protein (also known

119 of Abeta is directly controlled by the gamma-secretase complex and its activator, gamma-secretase act

120 Understanding of the structure of the gamma-secretase complex consisting of presenilin (PS), anterio

121 Whether the composition of a given gamma-secretase complex determines a specific cellular targeti

122 at presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheim

123 from intramembraneous cleavage by the gamma-secretase complex is not well defined.

124 The gamma-secretase complex is responsible for the cleavage of sev

125 Notch1 and Rheb esRNA and component of gamma-secretase complex presenilin 1 from Tsc1-null cells to w

126 main-shedding alpha-secretases and the gamma-secretase complex, a process called regulated intramembr

127 tify nicastrin, a key component of the gamma-secretase complex, as a membralin binding protein and me

128 1 (PS1), the catalytic subunit of the gamma-secretase complex, cleaves betaCTF to produce Abeta.

129 y the Presenilin 1 (PS1) enzyme in the gamma-secretase complex, generating Abeta.

130 nts for the conformation of the mature gamma-secretase complex, participating in the switch between t

131 ubsequent enzymatic proteolysis by the gamma-secretase complex, resulting in the cytoplasmic release

132 n role as the catalytic subunit of the gamma-secretase complex, selective phosphorylation of PS1 on S

133 n role as the catalytic subunit of the gamma-secretase complex, selective phosphorylation of PS1 on S

134 ne proteolysis of p75 catalyzed by the gamma-secretase complex.

135 hysiopathological configuration of the gamma-secretase complex.

136 ing cytoplasmic domain is processed by gamma-secretase complex.

137 gamma-Secretase complexes achieve the production of amyloid pe

138 e whether the cellular distribution of gamma-secretase complexes contributes to substrate selectivity

139 allow for the formation of functional gamma-secretase complexes displaying specific activities and m

140 issile bond choices by tissue-specific gamma-secretase complexes following the intracellular domain s

141 We show that PS1-containing gamma-secretase complexes were targeted to the plasma membrane

142 Cells co-express differing gamma-secretase complexes, including two homologous presenilin

143 lin-dependent subcellular targeting of gamma-secretase complexes.

144 nd metalloprotease 10 (ADAM10) and the gamma-secretase component presenilin-1.

145 Presenilin 1 (PS1) is an essential gamma-secretase component, the enzyme responsible for amyloid

146 Thus, AEP acts as a delta-secretase, contributing to the age-dependent pathogenic

147 dependence of C99 protein cleavage by gamma-secretase, critical to the formation of amyloid-beta pro

148 Recent determination of intact human gamma-secretase cryo-electron microscopy structure has opened

149 Similarly, chemical inhibition of beta-secretase decreased mitochondrial respiration, suggestin

150 The final cleavage is gamma-secretase dependent and releases the active Notch intrac

151 We provide evidence that gamma-secretase-dependent but RBPj-independent Notch intracell

152 To escape this restriction, Gag promotes secretase-dependent cleavage of APP, resulting in the ov

153 hich reciprocally permits the required gamma-secretase-dependent cleavage of LRP8, revealing an unpre

154 erentiation during development through gamma-secretase-dependent intramembrane proteolysis followed b

155 migration and induces their death via gamma-secretase-dependent regulated intramembrane proteolysis

156 Thus, localization of gamma-secretases determines substrate specificity, while FAD-c

157 of soluble BCMA (sBCMA); inhibition of gamma-secretase enhanced surface expression of BCMA and reduce

158 ltiple small-molecule inhibitors of the beta-secretase enzyme (BACE1) are under preclinical or clinic

159 The beta-secretase enzyme BACE1 requires acidic lumen pH for opti

160 o reduce amyloidogenesis by suppressing beta-secretase expression and activities.

161 enzyme 1 (BACE1) is the major neuronal beta-secretase for Abeta generation.

162 enzyme 1 (BACE1) is the major neuronal beta-secretase for amyloid-beta generation and is degraded in

163 ally, AIBP triggered relocalization of gamma-secretase from lipid rafts to nonlipid rafts where it cl

164 prerequisite for substrate binding and gamma-secretase function.

165 metalloproteinase (ADAM) proteins and gamma-secretase generates intracellular C-terminal fragments (

166 r protein (APP), first by the action of beta-secretase, generating the beta-C-terminal fragment (beta

167 effect on the physiologic functions of gamma-secretase has not been tested in human model systems.

168 detected age-dependent increase in an alpha-secretase in ASD brains.

169 defective of the nicastrin subunit of gamma-secretase in oligodendrocytes have hypomyelination in th

170 with the discovery of a number of novel APP secretases (including delta- and eta-secretases, alterna

171 SCNA (alpha-synuclein) and ADAM10 (alpha-secretase) increased (both ANOVA, P<0.02) but PSEN1 (pre

172 e data uncover a ligand-dependent, but gamma-secretase-independent, non-canonical Notch signaling inv

173 logic blockage of Notch activation via gamma-secretase inhibition.

174 ed the combination between miR-34a and gamma-secretase inhibitor (gammaSI), Sirtinol or zoledronic ac

175 Ex vivo, Gamma secretase inhibitor (GSI) (inhibitor of Notch receptor p

176 pharmacologic Notch inhibition using a gamma-secretase inhibitor (GSI) rescued the hyperproliferative

177 ory protein (c-FLIP) turnover and that gamma-secretase inhibitor blocked c-FLIP turnover and also par

178 Using gamma-secretase inhibitor DAPT to acutely block canonical Notc

179 a protocol that utilizes BMP4 and the gamma-secretase inhibitor DAPT to induce SE differentiation fr

180 e neuronal differentiation such as the gamma-secretase inhibitor DAPT.

181 g the NOTCH signaling pathway with the gamma-secretase inhibitor dibenzazepine increased the number o

182 Treatment of mice with the gamma-secretase inhibitor dibenzazepine to diminish Notch-driv

183 n orally bioactive and brain permeable delta-secretase inhibitor in mouse models of AD.

184 ption of HUVEC-based tube formation by gamma-secretase inhibitor L1790 confirmed the critical role of

185 Treatment with the gamma-secretase inhibitor LY3039478 led to inhibition of CCRCC

186 These effects were suppressed by the gamma-secretase inhibitor LY450139.

187 , these findings demonstrate that this delta-secretase inhibitor may be an effective clinical therape

188 e response rate after therapy with the gamma-secretase inhibitor PF-03084014 in patients with recurre

189 ere also seen after treatment with the gamma-secretase inhibitor PF-03084014.

190 the cleavage product from Ac-gamma-Glu-gamma-secretase inhibitor prodrug 13a (gamma-GT-targeting and

191 T-targeting) but not from Ac-alpha-Glu-gamma-secretase inhibitor prodrug 15a (APA-targeting) accumula

192 or specific inhibition of Notch1 by a gamma-secretase inhibitor substantially inhibits LFA-1/ICAM-1-

193 ential nephroprotective effects of the gamma-secretase inhibitor targeted prodrugs were investigated

194 thway triggers modest effects, combining a ?-secretase inhibitor to block Notch activation and a tyro

195 rom CSL/RBP-Jkappa KO mice phenocopied gamma-secretase inhibitor treatment for reduced IL-12p40/70 pr

196 tical neurons, and can be prevented by gamma-secretase inhibitor treatment.

197 rotein kinase (PKG) inhibitor, but not gamma-secretase inhibitor, abolished the elevation of synaptic

198 Treatment with the gamma-secretase inhibitor, DAPT, to inhibit cleavage and relea

199 d identified a non-toxic and selective delta-secretase inhibitor, termed compound 11, that specifical

200 appaB subunit c-Rel was compromised in gamma-secretase inhibitor-treated and CSL/RBP-Jkappa KO but no

201 es of blocking Abeta production with a gamma-secretase inhibitor.

202 ytotoxicity, which can be attenuated by beta-secretase inhibitor.

203 d upon treatment with the Ac-gamma-Glu-gamma-secretase-inhibitor 13a.

204 Inhibition of the Notch pathway by the gamma-secretase inhibitorN-[N-(3,5-difluorophenacetyl)-l-alany

205 Targeting glioblastoma stem cells with gamma-secretase inhibitors (GSIs) disrupts the Notch pathway a

206 er, inhibition of NOTCH signaling with gamma-secretase inhibitors (GSIs) has shown limited antileukem

207 a novel spirocyclic sulfone series of gamma-secretase inhibitors (GSIs) related to MRK-560.

208 leukemia (T-ALL) and Notch inhibitors (gamma-secretase inhibitors [GSIs]) have produced responses in

209 nt on secretase activity as ADAM10 and gamma-secretase inhibitors blocked RAGE ligand-mediated cell m

210 emic Notch blockade were observed with gamma-secretase inhibitors in preclinical and early clinical t

211 el therapies, including nelarabine and gamma-secretase inhibitors, in adult patients with T-cell ALL.

212 bsence or reduction of PS1, as well as gamma-secretase inhibitors, increases neuronal miR-212, which

213 gnaling, via knockdown of Notch1 or by gamma-secretase inhibitors, significantly reduced TGF-beta-ind

214 a surrogate for the design of renin and beta-secretase inhibitors.

215 residue CTF (C99)]- and Notch-specific gamma-secretase interaction assays identified a unique ErbB2-c

216 the amyloid precursor protein (APP) by gamma-secretase is a crucial first step in the evolution of Al

217 n embryonic kidney cells, we show that gamma-secretase is a very slow protease with a kcat value simi

218 ils implicated in Alzheimer's disease, gamma-secretase is an important target for developing therapeu

219 gamma-Secretase is an intramembrane-cleaving protease that pro

220 gamma-Secretase is an intramembrane-cleaving protease that pro

221 gamma-Secretase is an intramembranous protein complex composed

222 gamma-secretase is composed of four subunits: nicastrin (NCT)

223 Delta-secretase is highly phosphorylated in human AD brains, t

224 gamma-secretase is responsible for the proteolysis of amyloid

225 is by the canonical alpha-, beta-, and gamma-secretases is simplistic, with the discovery of a number

226 membrane-cleaving proteases (I-CLiPs), gamma-secretase, is also intimately implicated in Alzheimer's

227 proteolysis by the enzymes Adam10 and gamma-secretase, is rate-limiting in NOTCH activation.

228 the impact on memory of the Drosophila alpha-secretase kuzbanian (KUZ), the enzyme initiating the non

229 d subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular re

230 Amyloidogenic processing of APP through secretases leads to the generation of toxic amyloid beta

231 phenotype than either global Notch or gamma-secretase loss.

232 ken together, these data indicate that gamma-secretase-mediated cleavage provides an additional signa

233 The synthesis of the gamma-secretase modulator MK-8428 (1) is described.

234 therapeutic interest for the design of gamma-secretase modulators for Alzheimer disease.

235 ustry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism stu

236 of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replac

237 gamma-Secretase modulators, a class of Alzheimer's disease the

238 SAP formation, but not for other known gamma-secretase modulators, by directly and specifically activ

239 -inflammatory drugs (NSAIDs) are known gamma-secretase modulators; they influence Abeta populations.

240 whereas Lahiri and Sokol have studied alpha-secretase (non-amyloidogenic or anabolic) processing and

241 h novel mechanisms shared with neither gamma-secretase nor PS2.

242 Transmembrane cleavage by gamma-secretase occurs at three gamma-sites to generate extrac

243 alloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precursor p

244 at combinatorial actions of ADAM10 and gamma-secretase on SIRPalpha cleavage promote inflammatory sig

245 hich was secondary to a decrease in the beta-secretase pathway.

246 Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role

247 Ms on both endogenous Abeta levels and gamma-secretase physiologic functions including endogenous Not

248 site, providing the mechanism by which gamma-secretase preferentially cleaves APP in three amino acid

249 LEI has been seen to interact with the gamma-secretase presenilin 1 subunit (PS1).

250 Druggability simulations show that gamma-secretase presents several hot spots for either orthoste

251 Ligand-dependent activation, gamma-secretase-processed cleavage, and recombining binding pr

252 lexes that characterize the sequential gamma-secretase processing of APP.

253 ontrast, E-Abetan stabilizers increase gamma-secretase processivity.

254 of AD, the precise mechanism by which gamma-secretase produces Abeta has remained elusive.

255 eta (Abeta) precursor protein (APP) by gamma-secretase produces multiple species of Abeta: Abeta40, s

256 APP cleavage by alpha-secretase produces potentially neurotrophic secreted APP

257 sign of novel allosteric modulators of gamma-secretase protease activity.

258 The gamma-secretase protease and associated regulated intramembran

259 ion that links the presenilins and the gamma-secretase protease to pro-inflammatory cytokine signalin

260 Presenilin1/gamma-secretase protects neurons from glucose deprivation-indu

261 ate cleavage and its inhibition within gamma-secretase proteolipobeads were observed.

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

263 Notch1 signaling in KO mice via reduced beta-secretase proteolysis suggests that altered phenotype of

264 A10 immunoprecipitation yielded gamma-secretase proteolytic activity and vice versa.

265 ein activated by the membrane-inserted gamma-secretase proteolytic complex.

266 bound stub was subsequently cleaved by gamma-secretase reducing ligand-independent signaling of the r

267 gamma-Secretase regulates fate determination of neural progeni

268 iological and pathological activity of gamma-secretase represents a challenging task in Alzheimer dis

269 The structure of gamma-secretase revealed by cryo-EM approaches suggested a sub

270 ructures of TRPV1, beta-galactosidase, gamma-secretase, ribosome-EF-Tu complex, 20S proteasome and RN

271 The mechanism by which gamma-secretase selectively recognizes and recruits ectodomain

272 or protein-cleaving enzyme 1 (BACE-1), gamma-secretase, soluble Abeta42, soluble amyloid precursor pr

273 er, precise mechanistic information of gamma-secretase still remains unclear.

274 servations demonstrate that TNFR1 is a gamma-secretase substrate and suggest that gamma-secretase cle

275 gamma-Secretase substrate cleavage and its inhibition within g

276 Instead, gamma-secretase-substrate binding is driven by an apparent tig

277 eoretical basis for the development of gamma-secretase/substrate stabilizing compounds for the preven

278 -secretase subunits (e.g. APH-1) or on gamma-secretase substrates (e.g. APP) are known to be involved

279 An increasing number of gamma-secretase substrates have a role in cytokine signaling,

280 mportance of other APP metabolites and gamma-secretase substrates in the etiology of the disease has

281 well as all nine previously published gamma-secretase substrates.

282 The GXXXG motifs on gamma-secretase subunits (e.g. APH-1) or on gamma-secretase su

283 six different combinations of the four gamma-secretase subunits including EGFP-tagged nicastrin.

284 conditions of reduced glucose, the PS1/gamma-secretase system decreases neuronal losses by suppressin

285 GD conditions, which suggests the PS1/gamma-secretase system protects neurons from GD-induced death.

286 te considerable interest in developing gamma-secretase targeting therapeutics for the treatment of AD

287 e previously proposed "dysfunction" of gamma-secretase that characterizes FAD-associated PSEN.

288 del of AD pathology, phosphorylation of beta-secretase, the enzyme involved in the formation of amylo

289 in a preventive mode, i.e., gamma- and beta-secretase; the rationale behind these two targets; and t

290 ove the activity of one such protease, gamma secretase, through an allosteric binding site to prefere

291 d precursor protein (APP) is cleaved by beta-secretase to generate a 99-aa C-terminal fragment (C99)

292 al fragment is subsequently cleaved by gamma-secretase to generate a cytosolic TNFR1 intracellular do

293 fragment (C99) that is then cleaved by gamma-secretase to generate the beta-amyloid (Abeta) found in

294 nique motif in PSEN2 that directs this gamma-secretase to late endosomes/lysosomes via a phosphorylat

295 dam13 cytoplasmic domain is cleaved by gamma secretase, translocates into the nucleus and regulates m

296 n (APP) C-terminal fragments (CTFs) by gamma-secretase underlies the pathogenesis of Alzheimer's dise

297 brane-associated SIRPalpha fragment by gamma-secretase was identified.

298 eracts with the nicastrin component of gamma-secretase, we find that substrate ectodomain is entirely

299 as an important crossroad for APP and these secretases, with major implications for APP processing a

300 to homogeneous distributions of active gamma-secretase within supported biomembranes with native-like