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Biomedical subjects

Hui Zheng

Publications and source records attributed to Hui Zheng.

At least 19 recordsLinked to original sources
PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗
PubMed2026

Comparative effects of pharmacological interventions in the prophylactic treatment of tension-type headache: systematic review and network meta-analysis.

BACKGROUND: Tension-type headache (TTH) is the most common neurological disorder. The comparative effect of pharmacological interventions for TTH prophylaxis remains unclear. We aimed to assess the comparative effects of pharmacological interventions in the prophylactic treatment of TTH. METHODS: Ovid Medline, Embase, and Cochrane were searched from inception to 12 December, 2025. Randomized controlled trials (RCTs) of medications compared to placebo or another medication for preventing TTH were included. The primary outcome was headache days per month. A Bayesian random-effect model was employed as the primary analysis of chronic TTH. RESULTS: Thirty-five RCTs were included, 33 (88.6%) RCTs involved chronic TTH patients, and 24 RCTs provided available data for meta-analysis. Amitriptyline 100 mg presented more reduction of monthly headache days than placebo at 4 and 8 weeks (4 weeks: MD -6.59, 95% CrI -11.22 to -0.64; 8 weeks: MD -6.14, 95% CrI -10.27 to -0.87). BTX-A 100 U can reduce monthly headache days (MD -3.79, 95% CrI -7.16 to -0.33). Amitriptyline 100 mg was the highest-ranked treatment for monthly headache days at 4 (SUCRA 0.85), 8 (SUCRA 0.85), and 24 (SUCRA 0.87) weeks; 12 weeks was lidocaine 25 ml (SUCRA 0.75). Amitriptyline 100 mg and BTX-A 500 U showed a higher adverse event rate than placebo. CONCLUSION: Amitriptyline 100 mg and BTX-A 100 U may be options to reduce monthly headache days in patients with chronic TTH. Given the low to very low certainty of evidence, high risk of bias, and high heterogeneity, more studies are needed. TRIAL REGISTRATION: PROSPERO (CRD42025639586).

Humans↗
PubMed2003

Presenilins are required for the formation of comma- and S-shaped bodies during nephrogenesis.

Mammalian presenilins consist of two highly homologous proteins, PSEN1 and PSEN2, which share redundant activities in Notch processing and signaling. To bypass the early lethality of the Psen1- and Psen2-double (PSEN) null embryos, we used a human PSEN1 transgene to rescue the somite patterning defects in PSEN-null animals and to allow a determination of the function of presenilins in late embryogenesis. We report here that expression of the human PSEN1 transgene supported the survival of PSEN-null embryos to the perinatal stage. However, presenilin deficiency in the kidney led to severe nephrogenesis defects and virtually no comma- or S-shaped bodies, or mature glomeruli were formed. We document that the mesenchyme was induced which could further progress to renal vesicles in the PSEN-null kidney, indicating that the presenilins are not essential for the inductive interactions and mesenchyme to epithelium transition. However, renal vesicles failed to pattern to form proximal tubules and glomerular epithelium. A presenilin-dependent, signaling-competent form of Notch1 was detected in mesenchymal derivatives but not in the ureteric buds of wild-type mice. Consistent with an obligatory role of presenilins in Notch processing and activation, the active form of Notch1 and its downstream target Hesr1 were absent in the PSEN-null kidney. Importantly, sustained Notch1 signaling was required for the maintenance of Notch ligand Jag1 expression. These results identify presenilins as one determinant of renal vesicle patterning in the developing mouse kidney, and we hypothesize that they act through the Notch signaling pathway.

Animals↗
PubMed2003

Distinct rates of palmitate turnover on membrane-bound cellular and oncogenic H-ras.

H-Ras displays dynamic cycles of GTP binding and palmitate turnover. GTP binding is clearly coupled to activation, but whether the palmitoylated COOH terminus participates in signaling, especially when constrained by membrane tethering, is unknown. As a way to compare COOH termini of membrane-bound, lipid-modified H-Ras, palmitate removal rates were measured for various forms of H-Ras in NIH 3T3 cells. Depalmitoylation occurred slowly (t(1/2) approximately 2.4 h) in cellular (H-RasWT) or dominant negative (H-Ras17N) forms and more rapidly (t(1/2) approximately 1 h) in oncogenic H-Ras61L or H-RasR12,T59. Combining this data with GTP binding measurements, the palmitate half-life of H-Ras in the fully GTP-bound state was estimated to be less than 10 min. Slow palmitate removal from cellular H-Ras was not explained by sequestration in caveolae, as neither cellular nor oncogenic H-Ras showed alignment with caveolin by immunofluorescence. Conversely, although it had faster palmitate removal, oncogenic H-Ras was located in the same fractions as H-RasWT on four types of density gradients, and remained fully membrane-bound. Thus the different rates of deacylation occurred even though oncogenic and cellular H-Ras appeared to be in similar locations. Instead, these results suggest that acylprotein thioesterases access oncogenic H-Ras more easily because the conformation of its COOH terminus against the membrane is altered. This previously undetected difference could help produce distinctive effector interactions and signaling of oncogenic H-Ras.

3T3 Cells↗
PubMed2003

Anxiolytic-like action of orally administered dl-tetrahydropalmatine in elevated plus-maze.

dl-Tetrahydropalmatine (dl-THP), a naturally occurring alkaloid, has been intensively studied for its sedative and hypnotic effects. Putative explanation for its mechanism and target of action involves the dopaminergic neurotransmission system. In view of the close interactions between the dopaminergic and the GABAergic neurons in the amygdala, pharmacological effects of dl-THP were tested for activity at the GABAA receptor benzodiazepine site (BDS). Effects of dl-THP were examined in mice employing the elevated plus-maze, the holeboard and the horizontal-wire tests. In the elevated plus-maze, mice treated with low doses of dl-THP (0.5-10 mg/kg) exhibited significant increase in the percentage of entries and time spent in open arms without altering the number of closed-arm entries when compared to the control group, indicative of its selective anxiolytic effect. In the holeboard and horizontal wire tests, where exploratory behavior and potential muscle relaxant effect were assessed, respectively, only mice treated with as much as 50 mg/kg dl-THP manifested sedation and myorelaxation, as observed in the significant decrease in the number of head dips and the decrease in the percentage of mice grasping wire in comparison to control. Notably, coadministration of the BDS antagonist flumazenil abolished the dl-THP-induced anxiolysis as seen in the reversal of the increase of both the number of entries and time spent in open arms back to basal levels in the elevated plus-maze test. The results suggest that dl-THP at defined low dosages acts as anxiolytics in mice, and the BDS mediates, at least in part, such anxiolytic effect of dl-THP.

Administration, Oral↗
PubMed2003

Statistical tests for fMRI based on experimental randomization.

Statistical parametric mapping (SPM) analysis of fMRI data requires specifying correctly the temporal and spatial noise covariance structure. This is a difficult if not impossible task. When these assumptions are not satisfied, statistical inference can be invalid or inefficient. Permutation tests are free of strong assumptions on the distribution of signal noise. We propose permutation tests of fMRI data based on experimental randomization of the stimulus sequences. Smooth hemodynamic response curves are estimated using quadratic B-splines. We study fMRI data obtained from event-related potential (ERP) oddball paradigm. Tests of two-tone and three-tone stimulus sequences are conducted to illustrate the application of the proposed method. Comparisons of the SPM and proposed method show that a permutation test is more specific and less susceptible to artifacts.

Arousal↗
PubMed2003

Solving the hypersingular boundary integral equation in three-dimensional acoustics using a regularization relationship.

Regularization of the hypersingular integral in the normal derivative of the conventional Helmholtz integral equation through a double surface integral method or regularization relationship has been studied. By introducing the new concept of discretized operator matrix, evaluation of the double surface integrals is reduced to calculate the product of two discretized operator matrices. Such a treatment greatly improves the computational efficiency. As the number of frequencies to be computed increases, the computational cost of solving the composite Helmholtz integral equation is comparable to that of solving the conventional Helmholtz integral equation. In this paper, the detailed formulation of the proposed regularization method is presented. The computational efficiency and accuracy of the regularization method are demonstrated for a general class of acoustic radiation and scattering problems. The radiation of a pulsating sphere, an oscillating sphere, and a rigid sphere insonified by a plane acoustic wave are solved using the new method with curvilinear quadrilateral isoparametric elements. It is found that the numerical results rapidly converge to the corresponding analytical solutions as finer meshes are applied.

Journal Article↗
PubMed2003

Hepatocyte transformation and tumor development induced by hepatitis C virus NS3 c-terminal deleted protein.

AIM: To study the effect of hepatitis C virus nonstructural protein 3 c-terminal deleted protein (HCV NS3-5') on hepatocyte transformation and tumor development. METHODS: QSG7701 cells were transfected with plasmid pRcHCNS3-5' (expressing HCV NS3 c-terminal deleted protein) by lipofectamine and selected in G418. The expression of HCV NS3 gene and protein was determined by PCR and immunohistochemistry respectively. Biological behavior of transfected cells was observed through cell proliferation assay, anchorage-independent growth and tumor development in nude mice. The expression of HCV NS3 and c-myc proteins in the induced tumor was evaluated by immunohistochemistry. RESULTS: HCV NS3 was strongly expressed in QSG7701 cells transfected with plasmid pRcHCNS3-5' and the positive signal was located in cytoplasm. Cell proliferation assay showed that the population doubling time in pRcHCNS3-5' transfected cells was much shorter than that in pRcCMV and non-transfected cells (24 h, 26 h, 28 h respectively). The cloning ratio of cells transfected with pRcHCNS3-5', pRcCMV and non-transfected cells was 33 %, 1.46 %, 1.11 %, respectively, the former one was higher than that in the rest two groups (P<0.01). Tumor development was seen in nude mice inoculated with pRcHCNS3-5' transfected cells after 15 days. HE staining showed its feature of hepatocarcinoma, and immunohistochemistry confirmed the expressions of HCV NS3 and c-myc proteins in tumor tissue. The positive control group inoculated with HepG2 also showed tumor development, while no tumor developed in the nude mice injected with pRcCMV and non-transfected cells after 40 days. CONCLUSION: 1.HCV NS3 c-terminal deleted protein has transforming and oncogenic potential. 2. Human liver cell line QSG7701 may be used as a good model to study HCV NS3 pathogenesis.

Animals↗
PubMed2003

[Significance of phosphorylation of mitogen-activated protein kinase and signal transducer and activator of transcription 3 and cyclin D1 protein expression in Hodgkin's lymphomas].

BACKGROUND & OBJECTIVE: Signal cascades of mitogen-actived protein kinase(MAPK) and signal transducer and activator of transcription 3 (Stat3) are two main signal transduction pathways which were associated with cell proliferation and malignant transformation.MAPK and Stat3 proteins are activated by phosphorylation. The biological effects which are caused by multiple cytokines produced by Hodgkin's lymphoma(HL) cells are mediated through MAPK and Stat3 signal pathways. This study was designed to investigate significance of MAPK and Stat3 phosphorylation(p-MAPK and p-Stat3) and cyclin D1 protein expression in HL. METHODS: SP immunohistochemistry was used to detect expression of p-MAPK, p-Stat3, and cyclin D1 protein in 45 cases of HL of various types. RESULTS: The expression positive rates of p-MAPK, p-Stat3, and cyclin D1 proteins were 73.3%(33/45),64.4%(29/45), and 68.9%(31/45), respectively. The positive expression levels of p-MAPK and cyclin D1 protein gradually increased(P< 0.05), whereas that of p-stat3 had no significant difference(P >0.05) in four subsets(LR:lymphocyte-rich classical type; NS:nodular sclerosis type; MC:mixed cellularity type; LD:lymphocyte depletion type) of all cases. The expression of p-MAPK was positively related to that of cyclin D1 protein (r(s)=0.7254,P< 0.01), but the expression of p-Stat3 was not related to that of cyclin D1 protein (r(s)=0.2197,P >0.05). CONCLUSION: The data suggest that activation of MAPK may play an important role in genesis and progression of HL, but Stat3 activation is not associated with the progression of HL. MAPK may induce overexpression of cyclin D1 protein and results in persistent proliferation of RS/H cells in genesis and development of HL.

Adolescent↗
PubMed2003

[Hepatocyte transformation and tumor development induced by hepatitis C virus NS3 N-terminal protein].

OBJECTIVE: To study the effect of hepatitis C virus nonstructural protein 3 N-terminal protein (HCV NS3-5') on hepatocyte transformation and tumor development. METHODS: QSG7701 cells were transfected with plasmid pRcHCNS3-5' (expressing HCV NS3 N-terminal protein) by lipofectamine and selected in G418. The expression of HCV NS3 gene and protein was determined by PCR and immunohistochemistry respectively. Biological effect of transfected cells was observed through cell proliferation assay, anchor independent growth, and tumor development in nude mice. The expression of HCV NS3 and c-myc protein in the induced tumor was evaluated by immunohistochemistry. RESULTS: HCV NS3 was strongly expressed in QSG7701 cells transfected with plasmid pRcHCNS3-5' and the positive signal was located in cytoplasm. The HCV NS3 expression and c-myc protein in the induced cytoplasm. Cell proliferation assay showed that the population doubling time in the pRcHCNS3-5' transfected cells was much shorter than that in the pRcCMV and non-transfected cells (24 h, 26 h, 28 h respectively). The cloning efficiencies of transfected cells with pRcHCNS3-5', pRcCMV and non-transfected cells were 33.0%, 1.5%, 1.1% respectively (P < 0.01). Tumor developed in nude mice inoculated with pRcHCNS3-5'transfected cells 15 days after the inoculation. HE staining showed hepatocarcinoma character and immunohistochemistry confirmed HCV NS3 and c-myc expression in the tumor tissue. The positive control group also showed tumor development, while no tumor mass obtained in the nude mice inoculated with pRcCMV and non-transfected cells even 40 days after the injection. CONCLUSION: HCV NS3 N-terminal protein showed cell transformation and tumorigenic features.

Animals↗
PubMed2002

Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein.

Presenilins (PS1/PS2) play a critical role in proteolysis of beta-amyloid precursor protein (beta APP) to generate beta-amyloid, a peptide important in the pathogenesis of Alzheimer's disease. Nevertheless, several regulatory functions of PS1 have also been reported. Here we demonstrate, in neuroblastoma cells, that PS1 regulates the biogenesis of beta APP-containing vesicles from the trans-Golgi network and the endoplasmic reticulum. PS1 deficiency or the expression of loss-of-function variants leads to robust vesicle formation, concomitant with increased maturation and/or cell surface accumulation of beta APP. In contrast, release of vesicles containing beta APP is impaired in familial Alzheimer's disease (FAD)-linked PS1 mutant cells, resulting in reduced beta APP delivery to the cell surface. Moreover, diminution of surface beta APP is profound at axonal terminals in neurons expressing a PS1 FAD variant. These results suggest that PS1 regulation of beta APP trafficking may represent an alternative mechanism by which FAD-linked PS1 variants modulate beta APP processing.

Amyloid beta-Protein Precursor↗
PubMed2002

Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi.

The search for novel anxiolytics devoid of undesirable side-effects typical of classical benzodiazepines (BDZs) has been intense, and flavonoids, as a relative new class of ligands, have been shown to possess anxiolytic effects in vivo. The present study evaluated the pharmacological properties of a naturally occurring monoflavonoid, 5,7-dihydroxy-8-methoxyflavone or wogonin. The affinity (K(i)) of wogonin for the benzodiazepine site (BZD-S) on the gamma-aminobutyric acid(A) (GABA(A)) receptor complex was 0.92 microM. Using electrophysiological techniques, we showed that wogonin enhanced the GABA-activated current in rat dorsal root ganglion neurons, and in Xenopus laevis oocytes expressing recombinant rat GABA(A) receptors, the enhancement was partially reversed by the co-application of a 1 microM concentration of the BZD-S antagonist anexate (Ro15-1788). Acute toxicity and behavioral effects were examined in mice. Acute lethal activity was low, with an LD(50) of 3.9 g/kg. Oral administration of wogonin (7.5 to 30 mg/kg) elicited an anxiolytic response that was similar to that elicited by diazepam in the elevated plus-maze; a dose-dependent increase in open arm entries and time spent in open arms was observed. More importantly, its anxiolytic effect was blocked by the co-administration of Ro15-1788. In the holeboard test, not only did wogonin-treated mice experience an increased number of head-dips but they also spent more time at it, showing no signs of sedation. Furthermore, wogonin did not cause myorelaxant effects in the horizontal wire test. Taken together, these data suggest that wogonin exerts its anxiolytic effect through positive allosteric modulation of the GABA(A) receptor complex via interaction at the BZD-S. Its anxiolytic effect was not accompanied by sedative and myorelaxant side-effects typical of BDZs.

Animals↗
PubMed2002

Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis.

The Alzheimer's disease-linked gene presenilin 1 (PS1) is required for intramembrane proteolysis of APP and Notch. In addition, recent observations strongly implicate PS1 as a negative regulator of the Wnt/beta-catenin signaling pathway, although the mechanism underlying this activity is unknown. Here, we show that presenilin functions as a scaffold that rapidly couples beta-catenin phosphorylation through two sequential kinase activities independent of the Wnt-regulated Axin/CK1alpha complex. Thus, presenilin deficiency results in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlight an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.

Alzheimer Disease↗
PubMed2002

Redox properties of rubredoxin variants as a function of solvent composition and temperature: investigation of monopolar and dipolar interactions.

The role of solvent composition and temperature on equilibrium electron transfer in seven rubredoxin variants [ Clostridium pasteurianum ( Cp), V8D, V8R, V8A, V44A Cp, Pyrococcus furiosus ( Pf), and A44V Pf] were investigated to examine the role of both monopolar and dipolar interactions. The reduction potentials of all variants decreased as the polarity of the solvent decreased. The enthalpy and entropy associated with electron transfer were determined from temperature-controlled voltammetric studies. The entropic contribution [delta( Tdelta S degrees )] to the change in the reduction potential was larger for charged variants (V8D and V8R), while the enthalpic contribution [delta(-delta H degrees )] was larger for the other mutants. The large entropy change observed for monopolar variants is likely due to solvent reorganization that occurs between oxidation states. Entropic-enthalpic compensation phenomena, an observation that most proteins have an entropic term [delta( Tdelta S degrees )] and enthalpic term [delta(-delta H degrees )] with opposite signs, was observed. A correlation of the size of the amino acid side chain with delta E degrees ', delta(-delta H degrees ), and delta( Tdelta S degrees ) is also discussed.

Bacterial Proteins↗
PubMed2002

The aspartate-257 of presenilin 1 is indispensable for mouse development and production of beta-amyloid peptides through beta-catenin-independent mechanisms.

To differentiate multiple activities of presenilin 1 (PS1), we generated transgenic mice expressing two human PS1 alleles: one with the aspartate to alanine mutation at residue 257 (hPS1D257A) that impairs the proteolytic activity of PS1, and the other deleting amino acids 340-371 of the hydrophilic loop sequence (hPS1Deltacat) essential for beta-catenin interaction. We show here that although hPS1Deltacat is fully competent in rescuing the PS1-null lethal phenotype, hPS1D257A does not exhibit developmental activity. hPS1D257A also leads to the concurrent loss of the proteolytic processing of Notch and beta-amyloid precursor protein (APP) and the generation of beta-amyloid peptides (Abeta). Further, by measuring the levels of endogenous Abeta(X-40) and Abeta(X-42) in primary neuronal cultures, we confirmed the concept that PS1 is indispensable for the production of secreted Abeta.

Amyloid beta-Peptides↗
PubMed2002

Trypsin-sensitive and lipid-containing sites of the macrophage extracellular matrix bind apolipoprotein A-I and participate in ABCA1-dependent cholesterol efflux.

A unique property of the extracellular matrix of J774 and THP-1 cells has been identified, which contributes to the ability of these cells to promote cholesterol efflux. We demonstrate high level apolipoprotein (apo) A-I binding to macrophage cells (THP-1 and J774) and to their extracellular matrix (ECM). However, high level apoA-I binding is not observed on fibroblasts, HepG2 cells, or U937 cells (a macrophage cell line that does not efflux cholesterol to apoA-I or bind apoA-I on their respective ECM). Binding to the ECM of THP-1 or J774 macrophages depends on the presence of apoA-I C-terminal helices and is markedly reduced with a mutant lacking residues 187-243 (apoA-I Delta(187-243)), suggesting that the hydrophobic C terminus forms a hydrophobic interaction with the ECM. ApoA-I binding is lost upon trypsin treatment or with Triton X-100, a preparation method that de-lipidates the ECM. However, binding is recovered with re-lipidation, and is preserved with ECM prepared using cytochalasin B, which conserves the endogenous phospholipid levels of the ECM. We also demonstrate that specific cholesterol efflux to apoA-I is much reduced in cells released from their native ECM, but fully restored when ECM-depleted cells are added back to ECM in the presence of apoA-I. The apoA-I-mediated efflux is deficient in plated or suspension U937 macrophages, but is restored to high levels when the suspension U937 cells are reconstituted with the ECM of J774 cells. The ECM-dependent activity was much reduced in the presence of glyburide, indicating participation of ABCA1 (ATP-binding cassette transporter 1) in the efflux mechanism. These studies establish a novel binding site for apoA-I on the macrophage ECM that may function together with ABCA1 in promoting cholesterol efflux.

ATP Binding Cassette Transporter 1↗
PubMed2002

Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production.

The Alzheimer's disease (AD)-associated presenilin (PS) proteins are required for the gamma-secretase cleavages of the beta-amyloid precursor protein and the site 3 (S3) protease cleavage of Notch. These intramembrane cleavages release amyloid-beta peptide (Abeta), including the pathogenic 42-aa variant (Abeta(42)), as well as the beta-amyloid precursor protein and the Notch intracellular domains (AICD, NICD). Whereas Abeta is generated by endoproteolysis in the middle of the transmembrane domain, AICD and NICD are generated by cleavages at analogous positions close to the cytoplasmic border of the transmembrane domain. Numerous mutations causing familial AD (FAD) that all cause increased production of Abeta(42) have been found in the PS1 gene. Here we have investigated the previously uncharacterized, very aggressive FAD mutation L166P that causes onset of AD in adolescence. Strikingly, the PS1 L166P mutation not only induces an exceptionally high increase of Abeta(42) production but also impairs NICD production and Notch signaling, as well as AICD generation. Thus, FAD-associated PS mutants cannot only affect the generation of NICD, but also that of AICD. Moreover, further analysis with artificial L166 mutants revealed that the gamma-secretase cleavage at position 40/42 and the S3-like gamma-secretase cleavage at position 49 of the Abeta domain are both differentially affected by PS1 L166 mutants. Finally, we show that PS1 L166 mutants affect the generation of NICD and AICD in a similar manner, supporting the concept that S3 protease and S3-like gamma-secretase cleavages are mediated by identical proteolytic activities.

Alzheimer Disease↗