ライフサイエンスコーパス: gamma-secretase

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

2 PP) by beta-secretase 1 (BACE-1) followed by gamma-secretase.

3 that affect the proteolytic activity of the gamma-secretase.

4 n presenilin 1 (PS1), a catalytic subunit of gamma-secretase.

5 y a disintegrin and metalloproteinase 10 and gamma-secretase.

6 a (PEA15), and its mRNA are regulated by PS1/gamma-secretase.

7 pathological functional conformations of the gamma-secretase.

8 ally increase Abeta42 via complex effects on gamma-secretase.

9 -secretases can form distinct complexes with gamma-secretase.

10 iprotease complex containing both alpha- and gamma-secretase.

11 r protein (APP) by beta-secretase (BACE) and gamma-secretase.

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

13 M, where it is normally processed rapidly by gamma-secretase.

14 ation of hair cells induced by inhibition of gamma-secretase.

15 amyloid precursor protein (APP) by beta- and gamma-secretases.

16 ty for the inhibition of the PS-1 isoform of gamma-secretase (33-fold vs PS-2), which may alleviate t

17 lize in lipid raft fractions, with increased gamma-secretase accumulation upon CRF treatment.

18 PS1/gamma-secretase activates the transcription factor, cAMP

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

20 e gamma-secretase complex and its activator, gamma-secretase activating protein (GSAP).

21 We find residual carboxy- and endo-peptidase gamma-secretase activities, similar to the formerly char

22 Furthermore, membralin deficiency enhances gamma-secretase activity and neuronal degeneration.

23 nhibitor X (Inh X), a compound that inhibits gamma-secretase activity before exposing to MAG or CNS m

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

25 CRF treatment also increases gamma-secretase activity in vitro, revealing a second, r

26 ion that is partially reversed by inhibiting gamma-secretase activity in vivo with Dll4 identified as

27 h the mutation of the proposed pivot rescues gamma-secretase activity inNCT-deficient cells in a mann

28 vious reports, we and others have shown that gamma-secretase activity is enriched in mitochondria-ass

29 Modulation of gamma-secretase activity to reduce toxic amyloid-beta pe

30 Furthermore, beta- and gamma-secretase activity was decreased in APP.PS.Cd38(-)

31 regation, deposition in the ER, reduction of gamma-secretase activity, and impaired mitochondrial dis

32 phorylation of PS1 at Ser367 does not affect gamma-secretase activity, but has a dramatic effect on A

33 ations cause loss of Presenilin function and gamma-secretase activity, including impaired Abeta produ

34 in the absence of presenilin expression and gamma-secretase activity, TNF-mediated JNK activation wa

35 e same motif resulted in opposite effects on gamma-secretase activity, without affecting the assembly

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

37 ed Psen1 mRNA expression, but both abolished gamma-secretase activity.

38 Abeta levels through indirect inhibition of gamma-secretase activity.

39 solic side of TMD4 affect Abeta42-generating gamma-secretase activity.

40 Inhibition of gamma-secretase also decreases neuronal survival under G

41 These observations implicate gamma-secretase and its mediated neurodevelopmental path

42 Inhibition of gamma-secretase and metalloproteinase proteolysis in the

43 Pharmacological inhibition of gamma-secretase and NOTCH1 processing also abrogates SKB

44 r than Abeta1-48 were efficiently cleaved by gamma-secretase and produced varying ratios of Abeta1-40

45 ectively link CRF to increased Abeta through gamma-secretase and provide mechanistic insight into how

46 mbrane platform enabling characterization of gamma-secretase and substrate within proteolipobead asse

47 tant both in the association between A10 and gamma-secretase and the gamma --> alpha feedback mechani

48 tch signaling in vitro via inhibition of the gamma-secretase and the redistribution of presenilin 1 f

49 first step for the subsequent processing by gamma-secretase and the release of gene regulatory intra

50 gamma-Secretases are a family of intramembrane-cleaving

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

52 id is not an essential element necessary for gamma-secretase assembly, activity, and stability, and t

53 e lid deletion has any significant impact on gamma-secretase assembly, activity, and stability, and t

54 ent cells, and then assessed their impact on gamma-secretase assembly, activity, and stability.

55 o-immunoprecipitation studies establish that gamma-secretase associates with CRFR1; this is mediated

56 Here we report an atomic structure of human gamma-secretase at 3.4 A resolution, determined by singl

57 e type 1-oriented stub is further cleaved by gamma-secretase at an -like site five amino acids N-term

58 reover, it affects the cleavage precision of gamma-secretase at the gamma-site similar to certain Alz

59 f endogenous BACE1 coimmunoprecipitated with gamma-secretase but not A10, suggesting that beta- and a

60 n suggest that the enzymatic function of PS1/gamma-secretase can be modulated by its 'phosphorylated'

61 ain -named JCasp- is naturally produced by a gamma-secretase/caspase double-cut of APP.

62 Herein, we demonstrate that gamma-secretase catalysis is driven by the stabilization

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

64 o address the frequency of susceptibility to gamma-secretase cleavage among human RTKs.

65 The latter activity is regulated by gamma-secretase cleavage and the translocation of the cy

66 lf-renewal upon proteolytic activation via a gamma-secretase cleavage complex (PS1, PS2) and TACE (AD

67 odel, they confirm that in cells the initial gamma-secretase cleavage does not precisely define subse

68 Another protein that undergoes very similar gamma-secretase cleavage is the p75 neurotrophin recepto

69 these studies further support the sequential gamma-secretase cleavage model, they confirm that in cel

70 F) delivery to the trans-Golgi network where gamma-secretase cleavage occurs.

71 the APPV717I mutation affects both beta- and gamma-secretase cleavage of APP.

72 dy that detects the neo-epitope created upon gamma-secretase cleavage of NOTCH3 to release its intrac

73 degradation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate a

74 degradation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate A

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

76 nal fragment is a prerequisite for efficient gamma-secretase cleavage of TNFR1.

77 Although the mutation lies near the gamma-secretase cleavage site in the transmembrane domai

78 Because this residue is just before the gamma-secretase cleavage site, we then investigated whet

79 a manner that alters the positioning of the gamma-secretase cleavage sites with respect to the cente

80 weak hydrogen bonds are at or near preferred gamma-secretase cleavage sites, suggesting that the sequ

81 The C-terminus of Abeta is generated by gamma-secretase cleavage within the transmembrane domain

82 We previously showed the framework of the gamma-secretase cleavage, i.e. the stepwise successive p

83 into recipient cells, and upon activation by gamma-secretase cleavage, induces NOTCH-specific gene ex

84 ed for ADAM13 proteolysis of its substrates, gamma-secretase cleavage, or nuclear translocation of it

85 e TAM family members AXL or TYRO3 depends on gamma-secretase cleavage.

86 es, besides the canonical alpha-, beta-, and gamma-secretases, cleave the amyloid precursor protein (

87 generation revealed that the raft-associated gamma-secretase cleaves betaCTF in a stepwise sequential

88 Additionally, CRFR1 and gamma-secretase co-localize in lipid raft fractions, wit

89 n microscopy showed that portions of A10 and gamma-secretase colocalize.

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

91 ation of Abeta is directly controlled by the gamma-secretase complex and its activator, gamma-secreta

92 The gamma-secretase complex comprises a horseshoe-shaped tra

93 Understanding of the structure of the gamma-secretase complex consisting of presenilin (PS), a

94 Whether the composition of a given gamma-secretase complex determines a specific cellular t

95 own that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial A

96 determined that expression of a single human gamma-secretase complex in cell lines retains the intrin

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

98 The gamma-secretase complex is responsible for the cleavage

99 uttle Notch1 and Rheb esRNA and component of gamma-secretase complex presenilin 1 from Tsc1-null cell

100 In conclusion, our data show that each gamma-secretase complex produces a characteristic Abeta

101 The presenilin-containing gamma-secretase complex produces the amyloid beta-peptid

102 ectodomain-shedding alpha-secretases and the gamma-secretase complex, a process called regulated intr

103 e identify nicastrin, a key component of the gamma-secretase complex, as a membralin binding protein

104 enilin 1 (PS1), the catalytic subunit of the gamma-secretase complex, cleaves betaCTF to produce Abet

105 The gamma-secretase complex, composed of presenilin, nicastr

106 then by the Presenilin 1 (PS1) enzyme in the gamma-secretase complex, generating Abeta.

107 erminants for the conformation of the mature gamma-secretase complex, participating in the switch bet

108 and subsequent enzymatic proteolysis by the gamma-secretase complex, resulting in the cytoplasmic re

109 s known role as the catalytic subunit of the gamma-secretase complex, selective phosphorylation of PS

110 s known role as the catalytic subunit of the gamma-secretase complex, selective phosphorylation of PS

111 lin N-terminal fragment (PS1-NTF) within the gamma-secretase complex, thus gaining insight into the b

112 membrane proteolysis of p75 catalyzed by the gamma-secretase complex.

113 the physiopathological configuration of the gamma-secretase complex.

114 spanning cytoplasmic domain is processed by gamma-secretase complex.

115 derstanding the functional mechanisms of the gamma-secretase complex.

116 gamma-Secretase complexes achieve the production of amyl

117 gamma-Secretase complexes are involved in the generation

118 termine whether the cellular distribution of gamma-secretase complexes contributes to substrate selec

119 d quantitative differences between different gamma-secretase complexes could be used to advance drug

120 asmids allow for the formation of functional gamma-secretase complexes displaying specific activities

121 ive scissile bond choices by tissue-specific gamma-secretase complexes following the intracellular do

122 carboxypeptidase-like activities of the four gamma-secretase complexes present in humans.

123 We show that PS1-containing gamma-secretase complexes were targeted to the plasma me

124 The reduced cell surface levels of mature gamma-secretase complexes, in turn, compromise the intra

125 Cells co-express differing gamma-secretase complexes, including two homologous pres

126 resenilin-dependent subcellular targeting of gamma-secretase complexes.

127 grin and metalloprotease 10 (ADAM10) and the gamma-secretase component presenilin-1.

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

129 served dependence of C99 protein cleavage by gamma-secretase, critical to the formation of amyloid-be

130 Recent determination of intact human gamma-secretase cryo-electron microscopy structure has o

131 thways for stepwise successive processing by gamma-secretase define the species and quantity of Abeta

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

133 We provide evidence that gamma-secretase-dependent but RBPj-independent Notch int

134 ion, which reciprocally permits the required gamma-secretase-dependent cleavage of LRP8, revealing an

135 r differentiation during development through gamma-secretase-dependent intramembrane proteolysis foll

136 induces apoptosis through two pathways: the gamma-secretase-dependent pathway mediated by turnover o

137 rat SC migration and induces their death via gamma-secretase-dependent regulated intramembrane proteo

138 Thus, localization of gamma-secretases determines substrate specificity, while

139 proteolysis involving two ADAMs, along with gamma-secretase, during cranial neural crest cell EMT.

140 ecretase, interacted and cofractionated with gamma-secretase endogenously in cells and mouse brain.

141 lease of soluble BCMA (sBCMA); inhibition of gamma-secretase enhanced surface expression of BCMA and

142 enzyme 1 levels and an increase of beta- and gamma-secretase enzyme activities, leading to enhanced A

143 in the proteolytic processing of APP by the gamma-secretase enzyme, as suggested by a series of Gly(

144 ations (V44M and V44A) can open the T48 site gamma-secretase for the initial epsilon-cleavage, and co

145 nistically, AIBP triggered relocalization of gamma-secretase from lipid rafts to nonlipid rafts where

146 t a disease-linked mutation leads to loss of gamma-secretase function, cognitive decline, and neurode

147 be a prerequisite for substrate binding and gamma-secretase function.

148 cular basis for mechanistic understanding of gamma-secretase function.

149 ial proteolysis of APP by beta-secretase and gamma-secretase generates Abeta.

150 gamma-Secretase generates amyloid beta-protein (Abeta),

151 in and metalloproteinase (ADAM) proteins and gamma-secretase generates intracellular C-terminal fragm

152 their effect on the physiologic functions of gamma-secretase has not been tested in human model syste

153 t mice defective of the nicastrin subunit of gamma-secretase in oligodendrocytes have hypomyelination

154 c plasticity, highlighting the importance of gamma-secretase in the function of mature synapses.

155 thway mediated by turnover of c-FLIP and the gamma-secretase-independent pathway mediated by PSAP-Bax

156 These data uncover a ligand-dependent, but gamma-secretase-independent, non-canonical Notch signali

157 armacologic blockage of Notch activation via gamma-secretase inhibition.

158 Ex vivo, Gamma secretase inhibitor (GSI) (inhibitor of Notch rece

159 stigated the combination between miR-34a and gamma-secretase inhibitor (gammaSI), Sirtinol or zoledro

160 Treatment with a novel sulfonamide-type gamma-secretase inhibitor (GSI) attenuated the formation

161 over, pharmacologic Notch inhibition using a gamma-secretase inhibitor (GSI) rescued the hyperprolife

162 nhibitory protein (c-FLIP) turnover and that gamma-secretase inhibitor blocked c-FLIP turnover and al

163 Using gamma-secretase inhibitor DAPT to acutely block canonica

164 lidate a protocol that utilizes BMP4 and the gamma-secretase inhibitor DAPT to induce SE differentiat

165 promote neuronal differentiation such as the gamma-secretase inhibitor DAPT.

166 locking the NOTCH signaling pathway with the gamma-secretase inhibitor dibenzazepine increased the nu

167 Treatment of mice with the gamma-secretase inhibitor dibenzazepine to diminish Notc

168 Selective reduction of Abeta with a gamma-secretase inhibitor has no effect on the frequency

169 A negative drug trial with a broad spectrum gamma-secretase inhibitor in AD patients has severely da

170 Inhibition of Notch signaling by gamma-secretase inhibitor inhibited the proliferation an

171 disruption of HUVEC-based tube formation by gamma-secretase inhibitor L1790 confirmed the critical r

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

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

174 enhanced by the combination of ATRA and the gamma-secretase inhibitor N-(N-(3,5-difluorophenacetyl)-

175 Cell cultures were treated with gamma-secretase inhibitor or GSM.

176 jective response rate after therapy with the gamma-secretase inhibitor PF-03084014 in patients with r

177 ases were also seen after treatment with the gamma-secretase inhibitor PF-03084014.

178 mice, the cleavage product from Ac-gamma-Glu-gamma-secretase inhibitor prodrug 13a (gamma-GT-targetin

179 mma-GCT-targeting) but not from Ac-alpha-Glu-gamma-secretase inhibitor prodrug 15a (APA-targeting) ac

180 ng Notch signaling, through injection of the gamma-secretase inhibitor RO4929097, stimulates a subset

181 ing Ab or specific inhibition of Notch1 by a gamma-secretase inhibitor substantially inhibits LFA-1/I

182 Potential nephroprotective effects of the gamma-secretase inhibitor targeted prodrugs were investi

183 ages from CSL/RBP-Jkappa KO mice phenocopied gamma-secretase inhibitor treatment for reduced IL-12p40

184 ry cortical neurons, and can be prevented by gamma-secretase inhibitor treatment.

185 dent protein kinase (PKG) inhibitor, but not gamma-secretase inhibitor, abolished the elevation of sy

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

187 d selective targeting, we have developed the gamma-secretase inhibitor-based prodrugs 13a and 15a as

188 e NF-kappaB subunit c-Rel was compromised in gamma-secretase inhibitor-treated and CSL/RBP-Jkappa KO

189 n induction of apoptosis, in the presence of gamma-secretase inhibitor.

190 minutes of blocking Abeta production with a gamma-secretase inhibitor.

191 gulated upon treatment with the Ac-gamma-Glu-gamma-secretase-inhibitor 13a.

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

193 ich is abrogated by combination therapy with gamma secretase inhibitors.

194 , we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downs

195 Targeting glioblastoma stem cells with gamma-secretase inhibitors (GSIs) disrupts the Notch pat

196 However, inhibition of NOTCH signaling with gamma-secretase inhibitors (GSIs) has shown limited anti

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

198 sphere-like ReN cell aggregate cultures with gamma-secretase inhibitors (GSIs), but not SGSMs, induce

199 astic leukemia (T-ALL) and Notch inhibitors (gamma-secretase inhibitors [GSIs]) have produced respons

200 ependent on secretase activity as ADAM10 and gamma-secretase inhibitors blocked RAGE ligand-mediated

201 gamma-Secretase inhibitors hold promise for the treatmen

202 f systemic Notch blockade were observed with gamma-secretase inhibitors in preclinical and early clin

203 Moreover, multiple gamma-secretase inhibitors significantly increased alpha

204 Suppression of Notch signaling by gamma-secretase inhibitors substantially reduced cell co

205 of novel therapies, including nelarabine and gamma-secretase inhibitors, in adult patients with T-cel

206 The absence or reduction of PS1, as well as gamma-secretase inhibitors, increases neuronal miR-212,

207 tch signaling, via knockdown of Notch1 or by gamma-secretase inhibitors, significantly reduced TGF-be

208 the active chair conformation of the parent gamma-secretase inhibitors.

209 F [99-residue CTF (C99)]- and Notch-specific gamma-secretase interaction assays identified a unique E

210 tion and triggers CRF receptor 1 (CRFR1) and gamma-secretase internalization.

211 and APP-like protein 2 (APLP2) by beta- and gamma-secretases into amyloid beta(A) and Abeta-like pep

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

213 n human embryonic kidney cells, we show that gamma-secretase is a very slow protease with a kcat valu

214 a fibrils implicated in Alzheimer's disease, gamma-secretase is an important target for developing th

215 gamma-Secretase is an intramembrane-cleaving protease th

216 gamma-Secretase is an intramembrane-cleaving protease th

217 gamma-Secretase is an intramembranous protein complex co

218 gamma-secretase is composed of four subunits: nicastrin

219 talloprotease TNFalpha-converting enzyme and gamma-secretase is necessary for p75(NTR)-mediated apopt

220 gamma-secretase is responsible for the proteolysis of am

221 Here we show that the Aph1b-gamma-secretase is selectively involved in Nrg1 intracel

222 Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease,

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

224 intramembrane-cleaving proteases (I-CLiPs), gamma-secretase, is also intimately implicated in Alzhei

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

226 ing and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellu

227 5-49) directly into purified preparations of gamma-secretase leads to the formation of Abeta40 and Ab

228 ic reduction of carboxypeptidase function of gamma-secretase leads to the gain of toxic Abeta42/Abeta

229 milder phenotype than either global Notch or gamma-secretase loss.

230 Taken together, these data indicate that gamma-secretase-mediated cleavage provides an additional

231 ta43 are generated through three routes, and gamma-secretase modulator 1 enhances all the three route

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

233 he industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechani

234 uation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide

235 he design and synthesis of a novel series of gamma-secretase modulators (GSMs) that incorporates a py

236 Soluble gamma-secretase modulators (SGSMs) selectively decrease

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

238 tides, which is reminiscent of the effect of gamma-secretase modulators inhibitors.

239 gamma-Secretase modulators, a class of Alzheimer's disea

240 for GSAP formation, but not for other known gamma-secretase modulators, by directly and specifically

241 little differential sensitivity to multiple gamma-secretase modulators.

242 l anti-inflammatory drugs (NSAIDs) are known gamma-secretase modulators; they influence Abeta populat

243 through novel mechanisms shared with neither gamma-secretase nor PS2.

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

245 The proteolytic cleavage by gamma-secretase of its C-terminal fragment produces amyl

246 est that combinatorial actions of ADAM10 and gamma-secretase on SIRPalpha cleavage promote inflammato

247 , which was mediated by an activation of the gamma-secretase pathway.

248 nd SGSMs on both endogenous Abeta levels and gamma-secretase physiologic functions including endogeno

249 ctive site, providing the mechanism by which gamma-secretase preferentially cleaves APP in three amin

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

251 Druggability simulations show that gamma-secretase presents several hot spots for either or

252 Ligand-dependent activation, gamma-secretase-processed cleavage, and recombining bind

253 ) complexes that characterize the sequential gamma-secretase processing of APP.

254 In contrast, E-Abetan stabilizers increase gamma-secretase processivity.

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

256 loid-beta (Abeta) precursor protein (APP) by gamma-secretase produces multiple species of Abeta: Abet

257 sed design of novel allosteric modulators of gamma-secretase protease activity.

258 The gamma-secretase protease and associated regulated intram

259 egulation that links the presenilins and the gamma-secretase protease to pro-inflammatory cytokine si

260 gamma-Secretase proteases have been associated with path

261 Presenilin1/gamma-secretase protects neurons from glucose deprivatio

262 substrate cleavage and its inhibition within gamma-secretase proteolipobeads were observed.

263 nt to regulate comm expression and that both gamma-secretase proteolysis of Fra and Fra's function as

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

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

266 he nucleus of mutant htt cells, and reducing gamma-secretase PS1 levels compensated for the cytotoxic

267 brane-bound stub was subsequently cleaved by gamma-secretase reducing ligand-independent signaling of

268 gamma-Secretase regulates fate determination of neural p

269 e physiological and pathological activity of gamma-secretase represents a challenging task in Alzheim

270 ned enthusiasm for the potential of pursuing gamma-secretase research therapeutically.

271 The structure of gamma-secretase revealed by cryo-EM approaches suggested

272 -EM structures of TRPV1, beta-galactosidase, gamma-secretase, ribosome-EF-Tu complex, 20S proteasome

273 The mechanism by which gamma-secretase selectively recognizes and recruits ecto

274 recursor protein-cleaving enzyme 1 (BACE-1), gamma-secretase, soluble Abeta42, soluble amyloid precur

275 However, precise mechanistic information of gamma-secretase still remains unclear.

276 ese observations demonstrate that TNFR1 is a gamma-secretase substrate and suggest that gamma-secreta

277 gamma-Secretase substrate cleavage and its inhibition wi

278 Instead, gamma-secretase-substrate binding is driven by an appare

279 the theoretical basis for the development of gamma-secretase/substrate stabilizing compounds for the

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

281 An increasing number of gamma-secretase substrates have a role in cytokine signa

282 the importance of other APP metabolites and gamma-secretase substrates in the etiology of the diseas

283 new as well as all nine previously published gamma-secretase substrates.

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

285 on of six different combinations of the four gamma-secretase subunits including EGFP-tagged nicastrin

286 under conditions of reduced glucose, the PS1/gamma-secretase system decreases neuronal losses by supp

287 under GD conditions, which suggests the PS1/gamma-secretase system protects neurons from GD-induced

288 Despite considerable interest in developing gamma-secretase targeting therapeutics for the treatment

289 of the previously proposed "dysfunction" of gamma-secretase that characterizes FAD-associated PSEN.

290 t improve the activity of one such protease, gamma secretase, through an allosteric binding site to p

291 minal cleavage region, which is processed by gamma-secretase to a series of products.

292 terminal fragment is subsequently cleaved by gamma-secretase to generate a cytosolic TNFR1 intracellu

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

294 ed a unique motif in PSEN2 that directs this gamma-secretase to late endosomes/lysosomes via a phosph

295 the adam13 cytoplasmic domain is cleaved by gamma secretase, translocates into the nucleus and regul

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

297 he membrane-associated SIRPalpha fragment by gamma-secretase was identified.

298 in interacts with the nicastrin component of gamma-secretase, we find that substrate ectodomain is en

299 rise to homogeneous distributions of active gamma-secretase within supported biomembranes with nativ

300 Because GSAP interacts with gamma-secretase without affecting the cleavage of Notch,