ライフサイエンスコーパス: BACE

1 BACE activity correlated with formic acid-extractable A

2 BACE cleavage of the APP leads to formation of the Abeta

3 BACE inhibition led to a significant time- and dose-depe

4 BACE inhibition resulted in decreased labeled sAPPbeta a

5 BACE initiates the production of beta-amyloid (Abeta), t

6 BACE is a transmembrane protease with beta-secretase act

7 BACE is an aspartyl protease, and there is significant e

8 BACE is targeted through the secretory pathway to the pl

9 BACE levels are elevated in AD brain, and increasing evi

10 BACE, a beta-secretase, is an attractive potential disea

11 BACE-1 (beta-site amyloid precursor protein cleaving enz

12 BACE-1 cleavage of APP is the committed step in Abeta sy

13 BACE-1 has been shown to be the major beta-secretase and

14 BACE-1 inhibition has the potential to provide a disease

15 BACE-1 inhibitory potency was increased (0.9 microM to 1

16 BACE-1 is the beta-secretase responsible for the initial

17 BACE-1 levels also were a mean of 7-fold higher in ADEs

18 amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta

19 ession of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs.

20 amyloid precursor protein-cleaving enzyme 1 (BACE-1), gamma-secretase, soluble Abeta42, soluble amylo

21 e of APP by beta-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargemen

22 amyloid-precursor-protein-cleaving enzyme 1 (BACE-1), with many big pharma companies expending great

23 beta-Site APP cleaving enzyme-1 (BACE-1) is the predominant enzyme involved in beta-secre

24 d precursor protein (APP) cleaving enzyme-1 (BACE-1), and Abeta42 and tau aggregation inhibition).

25 ing also reduces levels of beta-secretase 1 (BACE-1) and BACE-1-cleaved amyloid precursor protein (AP

26 precursor protein (APP) by beta-secretase 1 (BACE-1) followed by gamma-secretase.

27 or its radical capture and beta-secretase 1 (BACE-1) inhibitory activities.

28 beta-Secretase 1 (BACE-1) is an attractive therapeutic target for the trea

29 P-9, in neuropathic pain), beta-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), ca

30 ceived a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover desig

31 Conversely, a BACE inhibitor decreased sAPPbeta and Abeta peptides wit

32 escribes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guani

33 ry 10 years ago, much has been learned about BACE.

34 1 binds to the BACE-1 promoter and activates BACE-1 transcription.

35 f Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidogenic APP processing, and enhan

36 ays, the properties of a potent, cell-active BACE-1 inhibitor are described.

37 not different between 3xTg-AD versus 3xTg-AD/BACE(-/-) mice, thereby demonstrating that tau pathology

38 P immunostaining was detected in the 3xTg-AD/BACE(-/-) mice.

39 Atabecestat is an orally administered BACE inhibitor developed to treat Alzheimer's disease.

40 activity has obvious therapeutic advantages, BACE-1 also cleaves numerous other substrates with impor

41 and APP and might therefore directly affect BACE-APP complex formation.

42 After BACE cleavage, APP becomes a substrate for gamma-secreta

43 However, although BACE inhibition can reduce cerebral Abeta levels, whethe

44 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Abeta

45 glycosaminoglycan-binding proteins FGF-1 and BACE, and for the heterotypic adhesion molecules JAM-B a

46 uces levels of beta-secretase 1 (BACE-1) and BACE-1-cleaved amyloid precursor protein (APP) metabolit

47 study, we found that the levels of Abeta and BACE-1 are significantly reduced in the brains of mice l

48 APP and BACE are co-internalized from the cell surface to early

49 ur strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic

50 e much research, neuronal locales of APP and BACE-1 convergence and APP cleavage remain unclear.

51 n hippocampal neurons, we found that APP and BACE-1 interacted in both biosynthetic and endocytic com

52 In axons, APP and BACE-1 were cotransported, and they also interacted duri

53 ylcholinesterase, butyrylcholinesterase, and BACE-1, dual Abeta42 and tau antiaggregating activity, a

54 nces tau phosphorylation, activates Cdk5 and BACE-1, and accelerates amyloidogenic APP processing.

55 pectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic

56 yl proteases such as cathepsin D (Cat D) and BACE-2.

57 ity used to identify inhibitors of furin and BACE.

58 nt with anti-Abeta antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination

59 ctivity using a beta-secretase inhibitor and BACE knock-out cells, indicating that meprin beta acts i

60 establish a linkage between Abeta levels and BACE, we examined BACE protein, mRNA expression and enzy

61 onstrate correlation between Abeta loads and BACE elevation and also suggest that as a consequence, B

62 Moreover, sorLA and BACE also coimmunoprecipitate.

63 The convergence of APP (substrate) and BACE-1 (enzyme) is a rate-limiting, obligatory event tri

64 These data indicate an absence of TACE and BACE competition for the APP substrate.

65 tion using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1-/- mice, which mount a robust a

66 e molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine th

67 ntrols the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motio

68 gulation of amyloid precursor protein (APP), BACE-1, a trending increase in beta-amyloid Abeta(42/40)

69 y deficits and reduces pathology (i.e., APP, BACE-1 and p-tau levels).

70 'Icelandic' mutation greatly attenuates APP-BACE-1 interactions, suggesting a mechanistic basis for

71 plementation, for visualizing in cellulo APP-BACE-1 interactions as a simple on/off signal.

72 ineate mechanistic events that abrogates APP/BACE-1 convergence in this setting.

73 However, as both APP/BACE-1 are highly expressed in brain, mechanisms preclud

74 sis via the secretory pathway, dendritic APP/BACE-1-containing vesicles are largely segregated in phy

75 afficking strategies that normally limit APP/BACE-1 proximity and also uncover a pathway routing APP

76 Exploring dynamic localization of APP/BACE-1 in cultured hippocampal neurons, we found that af

77 A partitioning/convergence of APP/BACE-1 vesicles is also apparent in control/AD brains, r

78 ances Abeta production by increasing the APP/BACE-1 convergence in endolysosomal compartments.

79 them resistant to BACE cleavage, as well as BACE inhibition, result in the loss of axonal puncta and

80 and an intrinsic inverse correlation between BACE expression and oxidative metabolism at the first sy

81 strong negative correlation existed between BACE labeling intensity and CO or SDH activity among ind

82 st that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a nove

83 Blocking BACE-1 action, on the other hand, blocks Egr-1-induced a

84 We found that both BACE mRNA and protein expression is elevated in vivo in

85 In normal bulb, BACE was expressed predominantly in the glomerular layer

86 tibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only.

87 eavage of amyloid precursor protein (APP) by BACE-1 (beta-site APP cleaving enzyme-1) is the rate-lim

88 stand the effect of sorLA on APP cleavage by BACE, we analyzed whether sorLA interacts with APP and/o

89 or the C-terminal APP fragment generated by BACE-1 (betaCTF), all of which elevate the levels of bet

90 RG1 and NRG3 are constitutively processed by BACE and accumulate on axons where they interact with Er

91 2' positions This substrate was processed by BACE-1 approximately 10 times more efficiently than was

92 nders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the p

93 ity and/or oxidative metabolism, we compared BACE expression with cytochrome c oxidase (CO) or succin

94 tion and also suggest that as a consequence, BACE elevation may lead to increased Abeta production an

95 Considering BACE-1 is optimally active in an acidic environment, our

96 ation and in cells exposed to a conventional BACE inhibitor.

97 review summarizes BACE properties, describes BACE translation dysregulation in AD, and discusses BACE

98 o suggests new possibilities for discovering BACE-1-targeted compounds with more complex mechanisms o

99 anslation dysregulation in AD, and discusses BACE physiological functions in sodium current, synaptic

100 ly potent, selective and in vivo efficacious BACE inhibitors.

101 Enhanced BACE labeling was confirmed by measurements of elevated

102 homology to the mammalian processing enzyme BACE, recognizes the PEXEL motif and cleaves it at the c

103 ite Abeta precursor protein cleaving enzyme (BACE) 1 and BACE2.

104 e amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immun

105 PP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and huma

106 ntially by beta-site of APP-cleaving enzyme (BACE) and gamma-secretase to release the Abeta peptides

107 eta precursor protein (APP)-cleaving enzyme (BACE) and gamma-secretase, the proteases responsible for

108 reduction of beta-site APP cleaving enzyme (BACE) in these ArcTau mice decreases soluble Abeta oligo

109 Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's dise

110 Beta-APP cleaving enzyme (BACE) is responsible for the first of two proteolytic cl

111 eta peptides, beta-site APP-cleaving enzyme (BACE), presenilin-1 (PS-1), caspase-3, and caspase-media

112 e amyloid precursor protein cleaving enzyme (BACE)-1, a key enzyme responsible for Abeta formation, p

113 cleavage in a beta-site APP-cleaving enzyme (BACE)-dependent manner.

114 oid precursor protein (APP)-cleaving enzyme (BACE).

115 ase named the beta-site APP-cleaving enzyme (BACE).

116 tein (APP) by beta-site APP cleaving enzyme (BACE)1 and gamma-secretase.

117 e amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing an aminoethylene (AE) tetr

118 iating with beta-site APP-converting enzyme (BACE)1, thereby modulating APP processing.

119 peptides by beta-site APP cleaving enzymes (BACE).

120 resonance energy transfer assay to evaluate BACE-APP interactions in cells.

121 e between Abeta levels and BACE, we examined BACE protein, mRNA expression and enzymatic activity in

122 tion of endogenous and ectopically expressed BACE in a variety of cell types, including primary neuro

123 hysical and NMR-based methods as a bona fide BACE inhibitor.

124 es were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease

125 mics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH o

126 n were used to identify novel inhibitors for BACE-1.

127 isothiourea hit with a K(d) of 15 microM for BACE-1.

128 adaptor protein GGA3, which is required for BACE lysosomal degradation, consequently stabilizing BAC

129 o gain insight into the key requirements for BACE-1 and GSK-3beta inhibition.

130 expending great resources in the search for BACE-1 inhibitors.

131 Furthermore BACE activity increased significantly with age in mouse,

132 c interventions target APP processing (e.g., BACE inhibitors), those strategies may alter APP/APLP ph

133 is occlusion resulted in elevated glomerular BACE labeling in the deprived bulbs relative to the nond

134 hat prevents BACE-APP interactions and hence BACE cleavage of APP.

135 site APP-cleaving enzyme 1 (BACE1, or herein BACE).

136 Human BACE, also known as beta-secretase, shows promise as a p

137 esponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis.

138 9) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-per

139 They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin.

140 Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the mol

141 To test whether sorLA impacts BACE-APP interactions, we used a fluorescence resonance

142 Herein, we review the major advances in BACE-1 drug discovery, from single-target small molecule

143 We show that increases in BACE and beta-secretase activity are due to posttranslat

144 vels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are inc

145 silencing of ShcC also led to reductions in BACE levels in H4-FL-APP cells.

146 oscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and comp

147 Isoflurane may increase BACE levels by reducing BACE degradation.

148 Increased BACE levels in p25 overexpressing mice correlated with e

149 induce apoptosis, which, in turn, increases BACE and gamma-secretase levels and Abeta secretion.

150 ary neurons, overexpression of Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidoge

151 While inhibiting BACE-1 activity has obvious therapeutic advantages, BACE

152 le to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE

153 en combined with a beta-secretase inhibitor, BACE IV.

154 st display library that selectively inhibits BACE-1 activity toward APP by binding the APP substrate

155 and also uncover a pathway routing APP into BACE-1-containing organelles, triggering amyloidogenesis

156 the amyloidogenic pathway-APP is routed into BACE-1-positive recycling endosomes via a clathrin-depen

157 By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosi

158 reatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates a

159 Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been

160 micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-ba

161 d series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper

162 ligands represent a new type of nonpeptidic BACE-1 inhibitor motif that has not been described in th

163 t of AD and could be safer than nonselective BACE inhibitor drugs.

164 Notably, BACE reduction decreases the postsynaptic mislocalizatio

165 as resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework.

166 on the cell surface, and that LRP is a novel BACE substrate.

167 ts in the redistribution and accumulation of BACE in the late endosomal/lysosomal compartments (lysos

168 ray with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)).

169 ggest that Egr-1 plays role in activation of BACE-1 and acceleration of Abeta synthesis in AD brain.

170 synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation o

171 ese data highlight the potential benefits of BACE inhibition for the effective treatment of a wide ra

172 two novel assays for the characterization of BACE-1 inhibitors are reported.

173 tial to a full in silico characterization of BACE-1.

174 H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disea

175 e describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a

176 highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low

177 eres resulted in several distinct classes of BACE-1 active site directed compounds with improved chem

178 ts a promising advance in the development of BACE-1 inhibitors.

179 e as a starting point for the development of BACE-1-directed Alzheimer's disease therapeutics.

180 inding pocket within the catalytic domain of BACE that is distinct from the enzymatic active site (i.

181 e, only (18)F-AV45 could detect an effect of BACE inhibitor treatment.

182 ine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the k

183 understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about targe

184 isms of cellular interactions and effects of BACE-1 inhibitors in AD.

185 The elevation of BACE enzymatic activity in AD is correlated with brain A

186 hemiluminescence assay for the evaluation of BACE-1 inhibition in cultured cells that assesses the le

187 Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxye

188 data suggest that an age-related increase of BACE activity contributes to the increased production an

189 Abeta surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaire

190 We hypothesized that CNS inhibition of BACE would result in decreased newly generated Abeta and

191 roduction of Abeta peptide, by inhibition of BACE, is an attractive therapeutic modality for the trea

192 Thus, blanket inhibition of BACE-1 function may have adverse side effects.

193 h-throughput screening for the inhibition of BACE-1.

194 Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp l

195 ially selective small molecule inhibitors of BACE that act through exosite, rather than active site,

196 pyridine lead series to potent inhibitors of BACE-1 was demonstrated.

197 Inhibitors of BACE-1 with 3 muM to 32 nM potencies in cells are shown,

198 nsition state isostere derived inhibitors of BACE-1.

199 se hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidoge

200 activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain.

201 ism may explain increased cerebral levels of BACE and Abeta following cerebral ischemia and existing

202 caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia.

203 Ai silencing of GGA3 also elevated levels of BACE and Abeta.

204 Isoflurane increased the levels of BACE and gamma-secretase and secreted Abeta in the H4-AP

205 Levels of BACE-1 and sAPPbeta were significantly higher and of GDN

206 nversely correlated with increased levels of BACE.

207 The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspa

208 Here we show that the Drosophila ortholog of BACE, dBACE, is required for glial survival.

209 thiol-containing fragments versus a panel of BACE-1 active site cysteine mutants under redox-controll

210 The therapeutic potential of BACE will also be considered.

211 dynamics and inhibitor binding properties of BACE-1.

212 Our findings reveal a negative regulation of BACE expression by physiological neuronal activity and a

213 Regulation of BACE may play an important role in regulating the levels

214 e offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulati

215 is not meant to be a comprehensive review of BACE.

216 The results point to a biological role of BACE in synapse function and plasticity as well as a pot

217 e nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp).

218 ation of the inhibitor in the active site of BACE-1.

219 The crystal structure of BACE in complex with this hydroxyethyl secondary amine i

220 We determined the apo structure of BACE to 1.75 A, and a structure of a hydroxyethylamine i

221 ne (ABP) moiety, X-ray crystal structures of BACE mutant-disulfide conjugates revealed that the fragm

222 for APP-related, protein-based substrates of BACE.

223 The carboxyl terminus of BACE contains a di-leucine-based signal for sorting of t

224 rscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.

225 ced tau phosphorylation but has no effect on BACE-1 activation and amyloidogenic APP processing.

226 , but may be mediated by specific effects on BACE-related amyloid processes.

227 yzed whether sorLA interacts with APP and/or BACE.

228 The aspartyl protease beta-secretase, or BACE, has been demonstrated to be a key factor in the pr

229 ld-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age.

230 nzymatic activity or the processing of other BACE substrates.

231 ulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations i

232 ity (K(i) = 17 pM) and high selectivity over BACE 2 (>7000-fold) and cathepsin D (>250000-fold).

233 Analysis of PDAPP/BACE(-/-) mice demonstrated that BACE1 is absolutely req

234 ogues, have been found to be brain penetrant BACE-1 inhibitors.

235 acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP.

236 A type I transmembrane aspartyl protease, BACE (beta-site APP cleaving enzyme), has been identifie

237 features of HS for inhibiting the protease, BACE-1.

238 discovered that sorLA significantly reduced BACE-APP interactions in Golgi.

239 flurane may increase BACE levels by reducing BACE degradation.

240 idated a GGA3-dependent mechanism regulating BACE levels and beta-secretase activity.

241 in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated fo

242 he generation of Abeta is the beta-secretase BACE, for which powerful inhibitors have been developed

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

244 rylation, and decreases both beta-secretase (BACE) and APOEepsilon4 gene expression.

245 d precursor protein (APP) by beta-secretase (BACE) and gamma-secretase.

246 etic inhibitors of the human beta-secretase (BACE) are described.

247 es for use in SAR studies of beta-secretase (BACE) inhibitors and also as versatile ligands for other

248 beta-Secretase (BACE) is a prerequisite for amyloidogenesis, and it is u

249 d 3xTg-AD mice deficient for beta-secretase (BACE), the protease required for Abeta generation from A

250 inant APP as a substrate for beta-secretase (BACE), we have identified a series of compounds that inh

251 shedding of surface APP in a beta-secretase (BACE)-dependent manner.

252 harmacological modulation of beta-secretase (BACE).

253 of the validated AD targets beta-secretase (BACE-1) and glycogen synthase kinase-3beta (GSK-3beta) b

254 amidine-based inhibitors of beta-secretase (BACE-1).

255 ved inhibitors of the enzyme beta-secretase (BACE-1).

256 the aspartic acid protease, beta-secretase (BACE-1).

257 rs (the APP cleaving enzymes beta-secretase [BACE] and presenilin-1 [PS-1], and putative clearance mo

258 the di-leucine motif plays a role in sorting BACE to lysosomes.

259 osomal degradation, consequently stabilizing BACE and elevating Abeta generation.

260 This review summarizes BACE properties, describes BACE translation dysregulatio

261 di-leucine motif is necessary for targeting BACE to the lysosomes.

262 ed reduction of amyloid-beta pathology in TG-BACE mice.

263 Collectively, our data indicate that BACE is transported to the late endosomal/lysosomal comp

264 These results suggest that BACE and TACE share a common TGN localization, but under

265 ng only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysi

266 vealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3),

267 In contrast, the BACE-LL/AA mutant, in which Leu(499) and Leu(500) in the

268 t 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohyda

269 r BACE elevation was due to mutations in the BACE-coding region, we sequenced the entire ORF region o

270 n, we sequenced the entire ORF region of the BACE gene in these same AD and nondemented patients and

271 We found no mutations in the ORF of the BACE gene.

272 We present the genomic organization of the BACE gene.

273 ted the iBSEC1 scFv, since it recognizes the BACE-1 cleavage site on APP but does not bind the adjace

274 Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-termi

275 Binding of peptides to the BACE exosite leads to a concentration-dependent inhibiti

276 rate that in COS-7 cells, Egr-1 binds to the BACE-1 promoter and activates BACE-1 transcription.

277 trials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition

278 Thus, BACE is a prime drug target for the therapeutic inhibiti

279 hippocampal primary neurons, Egr-1 binds to BACE-1 and p35 promoters, enhances tau phosphorylation,

280 ucture of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interacti

281 Direct binding of GGA1 to BACE was not required for these effects, but the integri

282 -NRG1 and NRG3 that render them resistant to BACE cleavage, as well as BACE inhibition, result in the

283 ent binding free energy profiles for various BACE-1-inhibitor complexes.

284 ificantly reduced secreted Abeta levels when BACE was overexpressed, suggesting that sorLA influences

285 this study, we set out to determine whether BACE is degraded by the lysosomal pathway and whether th

286 To examine whether BACE elevation was due to mutations in the BACE-coding r

287 Understanding the mechanism by which BACE-1 is activated leading to Abeta synthesis in the br

288 While BACE-1 is sorted into acidic recycling endosomes, APP is

289 lved in BACE trafficking, are reduced, while BACE levels are increased.

290 A combination of compound 2a with BACE IV also reduced Abeta levels in cells, more than th

291 erm pathological co-accumulation of APP with BACE, PS-1, and activated caspase.

292 alpha or enhancement of its association with BACE may be viable strategies to ameliorate imbalances i

293 Thus, sorLA interacts both with BACE and APP and might therefore directly affect BACE-AP

294 ional crystal structure of 7 in complex with BACE-1 revealed that the amino group of the inhibitor co

295 binding (GGA) protein family, interacts with BACE and influences its subcellular distribution.

296 e that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts

297 stions about the timing of intervention with BACE-1 inhibitors, and anti-amyloid therapies in general

298 s and eukaryotic pepsins, in particular with BACE-1, thereby confirming their phylogenetic proximity.

299 An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhi

300 ne, noncovalent inhibition of wild-type (WT) BACE-1 activity.