Journal articles: 'BACE'

1

Casas, Silvia, Paola Casini, Sandra Piquer, Jordi Altirriba, Maud Soty, Lisa Cadavez, Ramon Gomis, and Anna Novials. "BACE2 plays a role in the insulin receptor trafficking in pancreatic β-cells." American Journal of Physiology-Endocrinology and Metabolism 299, no. 6 (December 2010): E1087—E1095. http://dx.doi.org/10.1152/ajpendo.00420.2010.

Full text

Abstract:

BACE1 (β-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1) is a β-secretase protein that plays a central role in the production of the β-amyloid peptide in the brain and is thought to be involved in the Alzheimer's pathogenesis. In type 2 diabetes, amyloid deposition within the pancreatic islets is a pathophysiological hallmark, making crucial the study in the pancreas of BACE1 and its homologous BACE2 to understand the pathological mechanisms of this disease. The objectives of the present study were to characterize the localization of BACE proteins in human pancreas and determine their function. High levels of BACE enzymatic activity were detected in human pancreas. In normal human pancreas, BACE1 was observed in endocrine as well as in exocrine pancreas, whereas BACE2 expression was restricted to β-cells. Intracellular analysis using immunofluorescence showed colocalization of BACE1 with insulin and BACE2 with clathrin-coated vesicles of the plasma membrane in MIN6 cells. When BACE1 and -2 were pharmacologically inhibited, BACE1 localization was not altered, whereas BACE2 content in clathrin-coated vesicles was increased. Insulin internalization rate was reduced, insulin receptor β-subunit (IRβ) expression was decreased at the plasma membrane and increased in the Golgi apparatus, and a significant reduction in insulin gene expression was detected. Similar results were obtained after specific BACE2 silencing in MIN6 cells. All these data point to a role for BACE2 in the IRβ trafficking and insulin signaling. In conclusion, BACE2 is hereby presented as an important enzyme in β-cell function.

APA, Harvard, Vancouver, ISO, and other styles

2

John, Varghese, James P. Beck, Michael J. Bienkowski, Sukanto Sinha, and Robert L. Heinrikson. "Human β-Secretase (BACE) and BACE Inhibitors." Journal of Medicinal Chemistry 46, no. 22 (October 2003): 4625–30. http://dx.doi.org/10.1021/jm030247h.

Full text

APA, Harvard, Vancouver, ISO, and other styles

3

John, Varghese. "Human β-secretase (BACE) and BACE Inhibitors: Progress Report." Current Topics in Medicinal Chemistry 6, no. 6 (March 1, 2006): 569–78. http://dx.doi.org/10.2174/156802606776743084.

Full text

APA, Harvard, Vancouver, ISO, and other styles

4

Rosse, Gerard. "Dihydrooxazines As Inhibitors of BACE-1 or BACE-2." ACS Medicinal Chemistry Letters 4, no. 5 (March 19, 2013): 433–34. http://dx.doi.org/10.1021/ml400104f.

Full text

APA, Harvard, Vancouver, ISO, and other styles

5

Bradley, Peter. "Back to BACE: one approach to fighting Alzheimer's." British Journal of Healthcare Assistants 11, no. 1 (January 2, 2017): 10–11. http://dx.doi.org/10.12968/bjha.2017.11.1.10.

Full text

APA, Harvard, Vancouver, ISO, and other styles

6

Luo, Gang, Hongxia Xu, Yinuo Huang, Dapeng Mo, Ligang Song, Baixue Jia, Bo Wang, Zhanqiang Jin, and Zhongrong Miao. "Deposition of BACE-1 Protein in the Brains of APP/PS1 Double Transgenic Mice." BioMed Research International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/8380618.

Full text

Abstract:

The main causes of Alzheimer’s disease remain elusive. Previous data have implicated the BACE-1 protein as a central player in the pathogenesis of Alzheimer’s disease. However, many inhibitors of BACE-1 have failed during preclinical and clinical trials for AD treatment. Therefore, uncovering the exact role of BACE-1 in AD may have significant impact on the future development of therapeutic agents. Three- and six-month-old female APP/PS1 double transgenic mice were used to study abnormal accumulation of BACE-1 protein in brains of mice here. Immunofluorescence, immunohistochemistry, and western blot were performed to measure the distributing pattern and expression level of BACE-1. We found obvious BACE-1 protein accumulation in 3-month-old APP/PS1 mice, which had increased by the time of 6 months. Coimmunostaining results showed BACE-1 surrounded amyloid plaques in brain sections. The abnormal protein expression might not be attributable to the upregulation of BACE-1 protein, as no significant difference of protein expression was observed between wild-type and APP/PS1 mice. With antibodies against BACE-1 and CD31, we found a high immunoreactive density of BACE-1 protein on the outer layer of brain blood vessels. The aberrant distribution of BACE-1 in APP/PS1 mice suggests BACE-1 may be involved in the microvascular abnormality of AD.

APA, Harvard, Vancouver, ISO, and other styles

7

Osherovich, Lev. "Genentech plays BACE." Science-Business eXchange 4, no. 22 (June 2011): 619. http://dx.doi.org/10.1038/scibx.2011.619.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Wong, Philip. "[AM-10]: BACE." Alzheimer's & Dementia 1 (July 2005): S3. http://dx.doi.org/10.1016/j.jalz.2005.06.037.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

Joseph, Ogunleye Adewale, Kikiowo Babatomiwa, Adelakun Niyi, Omotuyi Olaposi, and Inyang Olumide. "Molecular Docking and 3D Qsar Studies of C000000956 as a Potent Inhibitor of Bace-1." Drug Research 69, no. 08 (February 19, 2019): 451–57. http://dx.doi.org/10.1055/a-0849-9377.

Full text

Abstract:

Abstract Background BACE-1 is an aspartate protease that is responsible for the proteolysis of amyloid precursor proteins (APP) into beta-amyloid (Aβ), a neurotoxic peptide in patients with Alzheimer’s disease (AD). As such, BACE-1 is a prime pharmacological target in the control of Aβ in the brain and its inhibition will be a sound approach in AD therapy. Methods The computational pipeline which comprised molecular docking (MD), Quantitative Structure Activity Relationship (QSAR) modelling and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) studies enabled the prediction of molecular interaction and relative inhibitory potentials of the hit compound. Results and Discussion The current study reports a naturally sourced small molecule inhibitor of BACE1 (C000000956) which was obtained through a computational pipeline. Also, pharmacological constraints such as pH dependent activity of the enzyme and blood brain barrier permeation which have been associated with the efficacy of previous BACE-1 inhibitors were well catered for. Our results suggest that orally delivered C000000956 is a potential small molecule inhibitor of BACE-1 which may find usefulness in AD-therapy.

APA, Harvard, Vancouver, ISO, and other styles

10

Saric, Arman, Lars zur Brügge, Dirk Müller-Pompalla, Thomas Rysiok, Solenne Ousson, Bruno Permanne, Anna Quattropani, Michael Busch, Dirk Beher, and Ishrut Hussain. "Development and Characterization of a Novel Membrane Assay for Full-Length BACE-1 at pH 6.0." Journal of Biomolecular Screening 18, no. 3 (September 27, 2012): 277–85. http://dx.doi.org/10.1177/1087057112462237.

Full text

Abstract:

β-Site amyloid precursor protein cleaving enzyme–1 (BACE-1) is a transmembrane aspartic protease that mediates the initial cleavage of the amyloid precursor protein (APP), leading to the generation of amyloid-β (Aβ) peptides that are thought to be causative of Alzheimer’s disease (AD). Consequently, inhibition of BACE-1 is an attractive therapeutic approach for the treatment of AD. In general, in vitro biochemical assays to monitor BACE-1 activity have used the extracellular domain of the protein that contains the catalytic active site. This form of BACE-1 is catalytically active at acidic pH and cleaves APP-based peptide substrates at the β-site. However, this form of BACE-1 does not mimic the natural physiology of BACE-1 and shows minimal activity at pH 6.0, which is more representative of the pH within the intracellular compartments where BACE-1 resides. Moreover, high-throughput screens with recombinant BACE-1 at pH 4.5 have failed to identify tractable leads for drug discovery, and hence, BACE-1 inhibitor development has adopted a rational drug design approach. Here we describe the development and validation of a novel membrane assay comprising full-length BACE-1 with measurable activity at pH 6.0, which could be used for the identification of novel inhibitors of BACE-1.

APA, Harvard, Vancouver, ISO, and other styles

11

Mphahlele, Malose, Emmanuel Agbo, and Samantha Gildenhuys. "Synthesis and Evaluation of the 4-Substituted 2-Hydroxy-5-Iodochalcones and Their 7-Substituted 6-Iodoflavonol Derivatives for Inhibitory Effect on Cholinesterases and β-Secretase." International Journal of Molecular Sciences 19, no. 12 (December 18, 2018): 4112. http://dx.doi.org/10.3390/ijms19124112.

Full text

Abstract:

A series of 2-aryl-3-hydroxy-6-iodo-4H-chromen-4-ones substituted at the 7-position with a halogen atom (X = F, Cl and Br) or methoxy group and their corresponding 4-substituted 2-hydroxy-5-iodochalcone precursors were evaluated in vitro for inhibitory effect against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase (BACE1) activities. Although moderate inhibitory effect was observed for the chalcones against AChE, derivatives 2h, 2j and 2n exhibited significant inhibitory effect against BChE and BACE-1. The 2-aryl-7-fluoro-8-iodoflavonols 3b and 3c, on the other hand, exhibited increased activity and selectivity against AChE and reduced effect on BACE-1. The flavonols 3h, 3i, 3k, 3l and 3p exhibited moderate inhibitory effect against AChE, but significant inhibition against BChE. Compounds 2j and 3l exhibited non-competitive mode of inhibition against BACE-1. Molecular docking predicted strong interactions with the protein residues in the active site of BACE-1 implying these compounds bind with the substrate. Similarly docking studies predicted interaction of the most active compounds with both CAS and PAS of either AChE or BChE with mixed type of enzyme inhibition confirmed by kinetic studies.

APA, Harvard, Vancouver, ISO, and other styles

12

Garda, Zoltán, Tamara Kócs, István Bányai, José A. Martins, Ferenc Krisztián Kálmán, Imre Tóth, Carlos F. G. C. Geraldes, and Gyula Tircsó. "Complexes of Bifunctional DO3A-N-(α-amino)propinate Ligands with Mg(II), Ca(II), Cu(II), Zn(II), and Lanthanide(III) Ions: Thermodynamic Stability, Formation and Dissociation Kinetics, and Solution Dynamic NMR Studies." Molecules 26, no. 16 (August 16, 2021): 4956. http://dx.doi.org/10.3390/molecules26164956.

Full text

Abstract:

The thermodynamic, kinetic, and structural properties of Ln3+ complexes with the bifunctional DO3A-ACE4− ligand and its amide derivative DO3A-BACE4− (modelling the case where DO3A-ACE4− ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd3+ complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg2+ and Ca2+ complexes of DO3A-ACE4− and DO3A-BACE4− complexes are lower than for DOTA4− and DO3A3−, while the Zn2+ and Cu2+ complexes have similar and higher stability than for DOTA4− and DO3A3− complexes. The stability constants of the Ln(DO3A-BACE)− complexes increase from Ce3+ to Gd3+ but remain practically constant for the late Ln3+ ions (represented by Yb3+). The stability constants of the Ln(DO3A-ACE)4− and Ln(DO3A-BACE)4− complexes are several orders of magnitude lower than those of the corresponding DOTA4− and DO3A3− complexes. The formation rate of Eu(DO3A-ACE)− is one order of magnitude slower than for Eu(DOTA)−, due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)− complexes to dissociate several orders of magnitude faster than Ln(DOTA)− and its absence in the Ln(DO3A-BACE)− complexes results in inertness similar to Ln(DOTA)− (as judged by the rate constants of acid assisted dissociation). The 1H NMR spectra of the diamagnetic Y(DO3A-ACE)− and Y(DO3A-BACE)− reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-Λ(λλλλ) and S-Δ(δδδδ). The conformation of the Cα-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)− than the amino group in Y(DO3A-ACE)− to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)−, Gd(DO3A-BACE)− is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE4− in the design of GBCAs and Ln3+-based tags for protein structural NMR analysis.

APA, Harvard, Vancouver, ISO, and other styles

13

Johnston, J. A., W. W. Liu, S. A. Todd, D. T. R. Coulson, S. Murphy, G. B. Irvine, and A. P. Passmore. "Expression and activity of β-site amyloid precursor protein cleaving enzyme in Alzheimer's disease." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1096–100. http://dx.doi.org/10.1042/bst0331096.

Full text

Abstract:

Several lines of evidence indicate that the Aβ peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer's disease). The N-terminus of Aβ is generated by cleavage of the Met-Asp bond at position 671–672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called β-secretase. Two ‘β-secretase’ proteases have been identified: BACE (β-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/β-secretase activity in brain regions affected by the disease. We have demonstrated that robust β-secretase activity is also detectable in platelets that contain APP and release Aβ. This review considers the current evidence for alterations in β-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

APA, Harvard, Vancouver, ISO, and other styles

14

Kametaka, S. "Characterization of the novel aspartic proteinases, BACE and BACE2." Neuroscience Research 38 (2000): S124. http://dx.doi.org/10.1016/s0168-0102(00)81592-8.

Full text

APA, Harvard, Vancouver, ISO, and other styles

15

Nowotny, Petra, Sumi Chakraverti, Jennifer M. Kwon, and Alison M. Goate. "Association studies of novel polymorphisms in BACE and BACE2." Neurobiology of Aging 21 (May 2000): 102–3. http://dx.doi.org/10.1016/s0197-4580(00)82260-5.

Full text

APA, Harvard, Vancouver, ISO, and other styles

16

Verheijen, Jan H., Linda GM Huisman, Natascha van Lent, Ulf Neumann, Paolo Paganetti, C. Erik Hack, Femke Bouwman, Jan Lindeman, Edward LEM Bollen, and Roeland Hanemaaijer. "Detection of a Soluble Form of BACE-1 in Human Cerebrospinal Fluid by a Sensitive Activity Assay." Clinical Chemistry 52, no. 6 (June 1, 2006): 1168–74. http://dx.doi.org/10.1373/clinchem.2006.066720.

Full text

Abstract:

Abstract Background: Formation of deposits of the insoluble amyloid β-peptide is believed to be causally related with neurodegeneration in Alzheimer disease (AD). The β-peptide originates from a larger amyloid precursor protein (APP) by the action of proteolytic enzymes. The first proteolytic event leading to amyloid formation is the cleavage of APP by the membrane-bound aspartyl protease BACE-1, also known as memapsin-2. Inhibition of BACE-1 is thought to be a therapeutic approach to AD. Measuring BACE-1 activity in biological samples would be useful to elucidate the mechanism of AD and for development of AD drugs. Methods: We developed a sensitive and specific activity assay for BACE-1. The assay is based on a genetically engineered proenzyme that is specifically activated by BACE-1. The resulting active enzyme is measured with a chromogenic substrate. The use of 2 coupled reactions produces a detection limit as low as 0.4 pmol/L. Results: The assay detected BACE-1 activity in extracts of human brain tissue as well as, unexpectedly, in human cerebrospinal fluid (CSF). Gel electrophoresis and Western blotting identified the BACE-1 present in CSF as a truncated soluble form of the originally membrane-bound BACE-1. Conclusion: Detection of the soluble form of BACE-1 in CSF, a relatively easily accessible biological fluid, may be useful for monitoring the effects of drug candidates in vivo and may have diagnostic or prognostic applications.

APA, Harvard, Vancouver, ISO, and other styles

17

Vanoni, Omar, Paolo Paganetti, and Maurizio Molinari. "Consequences of Individual N-glycan Deletions and of Proteasomal Inhibition on Secretion of Active BACE." Molecular Biology of the Cell 19, no. 10 (October 2008): 4086–98. http://dx.doi.org/10.1091/mbc.e08-05-0459.

Full text

Abstract:

BACE is an aspartic protease involved in the production of a toxic peptide accumulating in the brain of Alzheimer's disease patients. After attainment of the native structure in the endoplasmic reticulum (ER), BACE is released into the secretory pathway. To better understand the mechanisms regulating protein biogenesis in the mammalian ER, we determined the fate of five variants of soluble BACE with 4, 3, 2, 1, or 0 N-linked glycans. The number of N-glycans displayed on BACE correlated directly with folding and secretion rates and with the yield of active BACE harvested from the cell culture media. Addition of a single N-glycan was sufficient to recruit the calnexin chaperone system and/or for oligosaccharide de-glucosylation by the ER-resident α-glucosidase II. Addition of 1–4 N-glycans progressively enhanced the dissociation rate from BiP and reduced the propensity of newly synthesized BACE to enter aberrant soluble and insoluble aggregates. Finally, inhibition of the proteasome increased the yield of active BACE. This shows that active protein normally targeted for destruction can be diverted for secretion, as if for BACE the quality control system would be acting too stringently in the ER lumen, thus causing loss of functional polypeptides.

APA, Harvard, Vancouver, ISO, and other styles

18

Bodendorf, Ursula, Frauke Fischer, Dale Bodian, Gerd Multhaup, and Paolo Paganetti. "A Splice Variant of β-Secretase Deficient in the Amyloidogenic Processing of the Amyloid Precursor Protein." Journal of Biological Chemistry 276, no. 15 (January 10, 2001): 12019–23. http://dx.doi.org/10.1074/jbc.m008861200.

Full text

Abstract:

β-Secretase (BACE) initiates the amyloidogenic processing of the amyloid precursor protein leading to the generation of the β-amyloid, the main component of Alzheimer's disease senile plaques. BACE is a type I transmembrane aspartyl protease of 501 amino acids. Here we describe a novel BACE mRNA lacking 132 base pairs that is expressed in the pancreas but not in the brain. Sequence alignment indicates that the deleted fragment matches the terminal two-thirds of exon 3. The new BACE variant is short of a 44-amino acid region located between the two catalytic aspartyl residues. Accordingly, a 50-kDa form of BACE (BACE457) is detected in the human pancreas. When expressed in cells, BACE457 colocalizes with the marker for the endoplasmic reticulum BiP. Moreover, BACE457 remains in a proenzymatic and endoglycosidase H-sensitive state, suggesting that its transport along the secretory pathway is blocked at the level of the endoplasmic reticulum. Notably, this novel form of BACE does not contribute to the processing of the amyloid precursor protein. Our findings suggest that tissue-specific splicing of the BACE mRNA may explain the observation that in the human pancreas robust transcription of the BACE gene does not translate into recovered enzymatic activity.

APA, Harvard, Vancouver, ISO, and other styles

19

Tran, Thai-Son, Thanh-Dao Tran, The-Huan Tran, Thanh-Tan Mai, Ngoc-Le Nguyen, Khac-Minh Thai, and Minh-Tri Le. "Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity." Molecules 25, no. 18 (September 5, 2020): 4064. http://dx.doi.org/10.3390/molecules25184064.

Full text

Abstract:

Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer’s disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35–85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC50 3.47–4.59 (AChE) and 4.15–5.80 (BACE-1). Three compounds (B3, D5 and D6) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.

APA, Harvard, Vancouver, ISO, and other styles

20

Parsons, R. B., and B. M. Austen. "Protein lipidation of BACE." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1091–93. http://dx.doi.org/10.1042/bst0331091.

Full text

Abstract:

Our research has concentrated upon the protein lipid modification of BACE [β-site amyloid precursor protein cleaving enzyme (β-secretase)], of which very little is currently known. Lipidation influences the production of Aβ (amyloid β-protein) by promoting the dimerization of BACE.

APA, Harvard, Vancouver, ISO, and other styles

21

Austen, B. M., and R. B. Parsons. "Protein lipidation of BACE." Biochemical Society Transactions 33, no. 5 (October 1, 2005): 1091. http://dx.doi.org/10.1042/bst20051091.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Mullard, Asher. "BACE race gains steam." Nature Reviews Drug Discovery 15, no. 3 (March 2016): 151. http://dx.doi.org/10.1038/nrd.2016.46.

Full text

APA, Harvard, Vancouver, ISO, and other styles

23

Netzer, William J., Karima Bettayeb, Subhash C. Sinha, Marc Flajolet, Paul Greengard, and Victor Bustos. "Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage." Proceedings of the National Academy of Sciences 114, no. 6 (January 23, 2017): 1389–94. http://dx.doi.org/10.1073/pnas.1620963114.

Full text

Abstract:

Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer’s disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.

APA, Harvard, Vancouver, ISO, and other styles

24

Parsons, R. B., J. K. Farrant, G. C. Price, D. Subramaniam, and B. M. Austen. "Regulation of the lipidation of β-secretase by statins." Biochemical Society Transactions 35, no. 3 (May 22, 2007): 577–82. http://dx.doi.org/10.1042/bst0350577.

Full text

Abstract:

Statins inhibit the dimerization of β-secretase [BACE (β-site amyloid precursor protein-cleaving enzyme)] by inhibiting the lipidation of BACE and associated proteins. Our studies have demonstrated a clearly defined temporal sequence for these reactions in the assembly of the BACE complex, which may provide targets for the treatment of Alzheimer's disease.

APA, Harvard, Vancouver, ISO, and other styles

25

Tran, Thai-Son, Minh-Tri Le, Thi-Cam-Vi Nguyen, The-Huan Tran, Thanh-Dao Tran, and Khac-Minh Thai. "Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones." Molecules 25, no. 17 (August 27, 2020): 3916. http://dx.doi.org/10.3390/molecules25173916.

Full text

Abstract:

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer’s disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of N-substituted-4-phenothiazine-chalcones was synthesized and tested for AChE and BACE-1 inhibitory activities. In silico models, including two-dimensional quantitative structure–activity relationship (2D-QSAR) for AChE and BACE-1 inhibitors, and molecular docking investigation, were developed to elucidate the experimental process. The results indicated that 13 chalcone derivatives were synthesized with relatively high yields (39–81%). The bioactivities of these substances were examined with pIC50 3.73–5.96 (AChE) and 5.20–6.81 (BACE-1). Eleven of synthesized chalcones had completely new structures. Two substances AC4 and AC12 exhibited the highest biological activities on both AChE and BACE-1. These substances could be employed for further researches. In addition to this, the present study results suggested that, by using a combination of two types of predictive models, 2D-QSAR and molecular docking, it was possible to estimate the biological activities of the prepared compounds with relatively high accuracy.

APA, Harvard, Vancouver, ISO, and other styles

26

Cully, Megan. "Lilly buys back into the BACE race for Alzheimer's disease." Nature Reviews Drug Discovery 13, no. 11 (October 17, 2014): 804. http://dx.doi.org/10.1038/nrd4469.

Full text

APA, Harvard, Vancouver, ISO, and other styles

27

Sosibo, Sphelele, Daniel Gyamfi Amoako, Anou Moise Somboro, Darren Delai Sun, Jane Catherine Ngila, and Hezekiel Kumalo. "Understanding the Binding Mechanism of Antagonist (AZD3293) Against BACE-1: Molecular Insights into Alzheimer’s Drug Discovery." Letters in Drug Design & Discovery 17, no. 7 (July 6, 2020): 850–57. http://dx.doi.org/10.2174/1570180816666191029142640.

Full text

Abstract:

Background: β-site amyloid precursor protein cleaving enzyme (BACE 1) is the ratelimiting enzyme in the formation of neurotoxic β-amyloid (Aβ) residues (Aβ1-40 or Aβ1-42) considered as key players in the onset of Alzheimer’s Disease (AD). Consequently, BACE 1 is one of the principal targets of anti-AD therapy with many small molecule BACE 1 inhibitors (BACE 1Is) in clinical trials. AZD3293 (Lanabecestat) is a BACE 1I that concluded in phase 2/3 clinical trials. Due to the limited knowledge about the interaction of this drug with the BACE 1 enzyme, in the present study, we performed comprehensive Molecular Dynamics (MD) analysis to understand the binding mechanism of AZD3293 to BACE 1. Methods: A production run of 120 ns is carried out and results are analysed using Root Mean Square Deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) to explain the stability of enzyme ligand complex. Further, the distance (d1) between the flap tip (Thr72) and the hinge residue of the flexible loop (Thr328), in relation to θ1 (Thr72–Asp228- Thr328), and to the dihedral angle δ (Thr72-Asp35-Asp228-Thr328) were measured. Results: The presence of the ligand within the active site restricted conformational changes as shown by decreased values of RMSF and average RMSD of atomic positions when compared to the values of the apoenzyme. Further analysis via the flap dynamics approach revealed that the AZD3293 decreases the flexibility of binding residues and made them rigid by altering the conformational changes. Conclusion: The prospective binding modes of AZD3293 from this study may extend the knowledge of the BACE 1-drug interaction and pave the way to design analogues with similar inhibitory properties needed to slow the progression of Alzheimer’s disease.

APA, Harvard, Vancouver, ISO, and other styles

28

Devraj, Kavi, Slobodan Poznanovic, Christoph Spahn, Gerhard Schwall, Patrick N. Harter, Michel Mittelbronn, Katia Antoniello, et al. "BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease." Journal of Cerebral Blood Flow & Metabolism 36, no. 7 (October 13, 2015): 1281–94. http://dx.doi.org/10.1177/0271678x15606463.

Full text

Abstract:

Endothelial cells of the blood–brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood–brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer’s disease, current treatment approaches include inhibitors of BACE-1 (β-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic β-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood–brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D- dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer’s disease mouse model we show that BACE-1 is upregulated at the blood–brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood–brain barrier in β-amyloid generation and in vascular aspects of Alzheimer’s disease, particularly in the development of cerebral amyloid angiopathy.

APA, Harvard, Vancouver, ISO, and other styles

29

Schechter, Israel, and Etty Ziv. "Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional β-secretase candidate(s)." Biological Chemistry 389, no. 3 (March 1, 2008): 313–20. http://dx.doi.org/10.1515/bc.2008.025.

Full text

Abstract:

Abstract Many studies suggest that BACE 1 is the genuine β-secretase; however, this is not undisputed. The wild-type (WT) β-site of the amyloid precursor protein (APP) present in the worldwide population is cleaved very slowly (k cat/K m: approx. 50 m -1 s-1), while proteases acting on relevant substrates are much more efficient (k cat/K m: 104–106 m -1 s-1). Knock-out of BACE 1 in mouse markedly reduces Aβ formation. Nevertheless, studies in other systems show that knock-out experiments in rodents and corresponding genetic defects in human may reveal different phenotypes. Considering these issues, we searched for other β-secretase candidate(s), identified cathepsin D, and evaluated properties of cathepsin D related to BACE 1 that were not examined previously. The kinetic constants (k cat, K m, k cat/K m) for cleaving peptides with β-sites of the WT or the mutated Swedish families (SW) APP by human BACE 1 and cathepsin D were determined and found to be similar. Western blots reveal that in human brain cathepsin D is approximately 280-fold more abundant than BACE 1. Furthermore, pepstatin A strongly inhibits the cleavage of SW and WT peptides by both brain extracts and cathepsin D, but not by BACE 1. These findings indicate that β-secretase activity observed in brain extracts is mainly due to cathepsin D. Nevertheless, as both BACE 1 and cathepsin D show poor activity towards the WT β-site sequence, it is necessary to continue the search for additional β-secretase candidate(s).

APA, Harvard, Vancouver, ISO, and other styles

30

Dabus, Guilherme, Waleed Brinjikji, Arun P. Amar, Josser E. Delgado Almandoz, Orlando M. Diaz, Pascal Jabbour, Ricardo Hanel, et al. "Angiographic and clinical outcomes of balloon remodeling versus unassisted coil embolization in the ruptured aneurysm cohort of the GEL THE NEC study." Journal of NeuroInterventional Surgery 10, no. 5 (August 18, 2017): 446–50. http://dx.doi.org/10.1136/neurintsurg-2017-013326.

Full text

Abstract:

Background and purposeGEL THE NEC (GTN) was a multicenter prospective registry developed to assess the safety and efficacy of HydroSoft coils in treating intracranial aneurysms. We compared the angiographic and clinical outcomes of aneurysms treated with balloon assisted coil embolization (BACE) versus unassisted coil embolization (CE) in the ruptured aneurysm cohort.Materials and methodsGTN was performed at 27 centers in five countries. Patients aged 21–90 years with a ruptured aneurysm 3–15 mm in size were eligible for enrollment. We analyzed demographics/comorbidities, aneurysm location, and geometry, including maximum diameter, neck size, and dome to neck ratio, immediate and long term angiographic outcomes (graded by an independent core laboratory using the modified Raymond Scale), and procedure related adverse events. Angiographic and clinical outcomes were studied using χ2and t tests.ResultsOf the 599 patients in the GTN, 194 met the inclusion criteria. 84 were treated with BACE and 110 with CE. There were more prior smokers in the BACE group (p=0.01). The BACE group also had more vertebrobasilar aneurysms (p=0.006) and a larger mean neck size (p=0.02). More aneurysms were immediately completely occluded in the BACE group (p=0.02) Procedure- related major morbidity and mortality were no different between the techniques (p=0.4 and p=1, respectively).ConclusionsIn this prospective ruptured aneurysm cohort from the GTN, BACE resulted in greater occlusion rates compared with unassisted CE with similar morbi-mortality.

APA, Harvard, Vancouver, ISO, and other styles

31

Chong, L. D. "A BACE-is for Therapy." Science 330, no. 6005 (November 4, 2010): 732. http://dx.doi.org/10.1126/science.330.6005.732-b.

Full text

APA, Harvard, Vancouver, ISO, and other styles

32

Arif, Nadia, Andleeb Subhani, Waqar Hussain, and Nouman Rasool. "In Silico Inhibition of BACE-1 by Selective Phytochemicals as Novel Potential Inhibitors: Molecular Docking and DFT Studies." Current Drug Discovery Technologies 17, no. 3 (July 15, 2020): 397–411. http://dx.doi.org/10.2174/1570163816666190214161825.

Full text

Abstract:

Background: Alzheimer’s Disease (AD) has become the most common age-dependent disease of dementia. The trademark pathologies of AD are the presence of amyloid aggregates in neurofibrils. Recently phytochemicals being considered as potential inhibitors against various neurodegenerative, antifungal, antibacterial and antiviral diseases in human beings. Objective: This study targets the inhibition of BACE-1 by phytochemicals using in silico drug discovery analysis. Methods: A total of 3150 phytochemicals were collected from almost 25 different plants through literature assessment. The ADMET studies, molecular docking and density functional theory (DFT) based analysis were performed to analyze the potential inhibitory properties of these phytochemicals. Results: The ADMET and docking results exposed seven compounds that have high potential as an inhibitory agent against BACE-1 and show binding affinity >8.0 kcal/mol against BACE-1. They show binding affinity greater than those of various previously reported inhibitors of BACE-1. Furthermore, DFT based analysis has shown high reactivity for these seven phytochemicals in the binding pocket of BACE- 1, based on ELUMO, EHOMO and Kohn-Sham energy gap. All seven phytochemicals were testified (as compared to experimental ones) as novel inhibitors against BACE-1. Conclusion: Out of seven phytochemicals, four were obtained from plant Glycyrrhiza glabra i.e. Shinflavanone, Glabrolide, Glabrol and PrenyllicoflavoneA, one from Huperzia serrate i.e. Macleanine, one from Uncaria rhynchophylla i.e. 3a-dihydro-cadambine and another one was from VolvalerelactoneB from plant Valeriana-officinalis. It is concluded that these phytochemicals are suitable candidates for drug/inhibitor against BACE-1, and can be administered to humans after experimental validation through in vitro and in vivo trials.

APA, Harvard, Vancouver, ISO, and other styles

33

Sluzewski, Menno, Willem Jan Van Rooij, Guus N. Beute, and Peter C. Nijssen. "Balloon-assisted coil embolization of intracranial aneurysms: incidence, complications, and angiography results." Journal of Neurosurgery 105, no. 3 (September 2006): 396–99. http://dx.doi.org/10.3171/jns.2006.105.3.396.

Full text

Abstract:

Object The aim of this study was to assess the incidence, indications, complications, and angiography results associated with balloon-assisted coil embolization (BACE) of intracranial aneurysms and to compare these factors with those for conventional coil embolization (CE). Methods Between 1995 and 2005, 827 intracranial aneurysms in 757 consecutive patients were packed with coils. Balloon-assisted coil embolization was used in 8.6% (71 of 827) of the coil insertion procedures and was more frequently used in large aneurysms, unruptured lesions, and those located on the vertebrobasilar system and carotid artery. Procedure-related complications leading to death or dependency were significantly higher in BACEs (14.1%) compared with those in CEs (3%). Packing densities and the results of 6-month follow-up angiography studies did not differ significantly between the two types of treatments. There was a strong trend for a higher retreatment rate in the aneurysms treated with BACE. Conclusions Balloon-assisted coil embolization of intracranial aneurysms is associated with a high complication rate and should only be used if conventional CE of these lesions is impossible or has failed and if anticipated surgical risks are too high. The BACE procedure does not improve the occlusion rates of the aneurysms on follow-up evaluation.

APA, Harvard, Vancouver, ISO, and other styles

34

Gonzalez, L. Fernando, Cameron G. McDougall, Felipe C. Albuquerque, Louis J. Kim, and Robert F. Spetzler. "Balloon-Assisted Coil Embolization." Journal of Neurosurgery 106, no. 4 (April 2007): 733–34. http://dx.doi.org/10.3171/jns.2007.106.4.733.

Full text

Abstract:

Object. The aim of this study was to assess the incidence, indications, complications, and angiography results associated with balloon-assisted coil embolization (BACE) of intracranial aneurysms and to compare these factors with those for conventional coil embolization (CE). Methods. Between 1995 and 2005, 827 intracranial aneurysms in 757 consecutive patients were packed with coils. Balloon-assisted coil embolization was used in 8.6% (71 of 827) of the coil insertion procedures and was more frequently used in large aneurysms, un-ruptured lesions, and those located on the vertebrobasilar system and carotid artery. Procedure-related complications leading to death or dependency were significantly higher in BACEs (14.1%) compared with those in CEs (3%). Packing densities and the results of 6-month follow-up angiography studies did not differ significantly between the two types of treatments. There was a strong trend for a higher retreatment rate in the aneurysms treated with BACE. Conclusions. Balloon-assisted coil embolization of intracranial aneurysms is associated with a high complication rate and should only be used if conventional CE of these lesions is impossible or has failed and if anticipated surgical risks are too high. The BACE procedure does not improve the occlusion rates of the aneurysms on follow-up evaluation.

APA, Harvard, Vancouver, ISO, and other styles

35

Tran, Thai-Son, Minh-Tri Le, Thanh-Dao Tran, The-Huan Tran, and Khac-Minh Thai. "Design of Curcumin and Flavonoid Derivatives with Acetylcholinesterase and Beta-Secretase Inhibitory Activities Using in Silico Approaches." Molecules 25, no. 16 (August 10, 2020): 3644. http://dx.doi.org/10.3390/molecules25163644.

Full text

Abstract:

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are the two crucial enzymes involved in the pathology of Alzheimer’s disease. The former is responsible for many defects in cholinergic signaling pathway and the latter is the primary enzyme in the biosynthesis of beta-amyloid as the main component of the amyloid plaques. These both abnormalities are found in the brains of Alzheimer’s patients. In this study, in silico models were developed, including 3D-pharmacophore, 2D-QSAR (two-dimensional quantitative structure-activity relationship), and molecular docking, to screen virtually a database of compounds for AChE and BACE-1 inhibitory activities. A combinatorial library containing more than 3 million structures of curcumin and flavonoid derivatives was generated and screened for drug-likeness and enzymatic inhibitory bioactivities against AChE and BACE-1 through the validated in silico models. A total of 47 substances (two curcumins and 45 flavonoids), with remarkable predicted pIC50 values against AChE and BACE-1 ranging from 4.24–5.11 (AChE) and 4.52–10.27 (BACE-1), were designed. The in vitro assays on AChE and BACE-1 were performed and confirmed the in silico results. The study indicated that, by using in silico methods, a series of curcumin and flavonoid structures were generated with promising predicted bioactivities. This would be a helpful foundation for the experimental investigations in the future. Designed compounds which were the most feasible for chemical synthesis could be potential candidates for further research and lead optimization.

APA, Harvard, Vancouver, ISO, and other styles

36

Arya, Richa, Satya Prakash Gupta, Sarvesh Paliwal, Seema Kesar, Achal Mishra, and Yenamandra Subrahmanya Prabhakar. "QSAR and Molecular Modeling Studies on a Series of Pyrrolidine Analogs Acting as BACE-1 Inhibitors." Letters in Drug Design & Discovery 16, no. 7 (June 27, 2019): 746–60. http://dx.doi.org/10.2174/1570180815666180627124422.

Full text

Abstract:

Background: β-Site amyloidal precursor protein (APP) cleavage enzyme (BACE-1) is reported as prime cause for progession of Alzheimer’s disease (AD). It is a form of dementia characterized by degeneration of neurones in brain. Therefore, attempts have been made to find potent inhibitors of this enzyme. Methods: The paper presents an division-based 2D quantitative structure-activity relationship (QSAR) study on a series of BACE-1 inhibitors to analyse the structural features that may be important to increase the potency of the compounds. Results: The study led to predict some potential leads for the development of potent inhibitors of BACE-1. One of the molecule with pyrrolidine and pyrrolidinone substitutions exhibited drugreceptor interactions comparable with reference drug. Conclusion: The hydrogen-bond interactions between the molecules and the receptor basically control the BACE-1 inhibition activity of the compounds.

APA, Harvard, Vancouver, ISO, and other styles

37

Lee, Edward B., Bin Zhang, Kangning Liu, Eric A. Greenbaum, Robert W. Doms, John Q. Trojanowski, and Virginia M. Y. Lee. "BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo." Journal of Cell Biology 168, no. 2 (January 10, 2005): 291–302. http://dx.doi.org/10.1083/jcb.200407070.

Full text

Abstract:

Introducing mutations within the amyloid precursor protein (APP) that affect β- and γ-secretase cleavages results in amyloid plaque formation in vivo. However, the relationship between β-amyloid deposition and the subcellular site of Aβ production is unknown. To determine the effect of increasing β-secretase (BACE) activity on Aβ deposition, we generated transgenic mice overexpressing human BACE. Although modest overexpression enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased β-cleavage of APP. However, high BACE expression shifted the subcellular location of APP cleavage to the neuronal perikarya early in the secretory pathway. These results suggest that the production, clearance, and aggregation of Aβ peptides are highly dependent on the specific neuronal subcellular domain wherein Aβ is generated and highlight the importance of perikaryal versus axonal APP proteolysis in the development of Aβ amyloid pathology in Alzheimer's disease.

APA, Harvard, Vancouver, ISO, and other styles

38

Willis, Brian A., Stephen L. Lowe, Scott A. Monk, Patrick J. Cocke, Christopher D. Aluise, Leonard N. Boggs, Anthony R. Borders, et al. "Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species." Journal of Alzheimer's Disease Reports 6, no. 1 (January 11, 2022): 1–15. http://dx.doi.org/10.3233/adr-210037.

Full text

Abstract:

Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer’s disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors. Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans. Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey’s post hoc test and clinical data used summary statistics. Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ1–40 and 0.228±0.244 nM for Aβ1–42 in PDAPP neuronal cultures. In dogs, CSF Aβ1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ1–42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans. Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development.

APA, Harvard, Vancouver, ISO, and other styles

39

Saunders, A. J. "BACE Maps to Chromosome 11 and a BACE Homolog, BACE2, Reside in the Obligate Down Syndrome Region of Chromosome 21 ." Science 286, no. 5443 (November 12, 1999): 1255a—1255. http://dx.doi.org/10.1126/science.286.5443.1255a.

Full text

APA, Harvard, Vancouver, ISO, and other styles

40

Enthoven, Wendy T. M., Jantine Scheele, Sita M. A. Bierma-Zeinstra, Herman J. Bueving, Arthur M. Bohnen, Wilco C. Peul, Maurits W. van Tulder, Marjolein Y. Berger, Bart W. Koes, and Pim A. J. Luijsterburg. "Analgesic Use in Older Adults with Back Pain: The BACE Study." Pain Medicine 15, no. 10 (October 2014): 1704–14. http://dx.doi.org/10.1111/pme.12515.

Full text

APA, Harvard, Vancouver, ISO, and other styles

41

Nawrot, Barbara. "Targeting BACE with small inhibitory nucleic acids - a future for Alzheimer's disease therapy?" Acta Biochimica Polonica 51, no. 2 (June 30, 2004): 431–44. http://dx.doi.org/10.18388/abp.2004_3582.

Full text

Abstract:

beta-Secretase, a beta-site amyloid precursor protein (APP) cleaving enzyme (BACE), participates in the secretion of beta-amyloid peptides (Abeta), the major components of the toxic amyloid plaques found in the brains of patients with Alzheimer's disease (AD). According to the amyloid hypothesis, accumulation of Abeta is the primary influence driving AD pathogenesis. Lowering of Abeta secretion can be achieved by decreasing BACE activity rather than by down-regulation of the APP substrate protein. Therefore, beta-secretase is a primary target for anti-amyloid therapeutic drug design. Several approaches have been undertaken to find an effective inhibitor of human beta-secretase activity, mostly in the field of peptidomimetic, non-cleavable substrate analogues. This review describes strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids (siNAs). These include antisense oligonucleotides, catalytic nucleic acids - ribozymes and deoxyribozymes - as well as small interfering RNAs (siRNAs). While antisense oligonucleotides were first used to identify an aspartyl protease with beta-secretase activity, all the strategies now demonstrate that siNAs are able to inhibit BACE gene expression in a sequence-specific manner, measured both at the level of its mRNA and at the level of protein. Moreover, knock-down of BACE reduces the intra- and extracellular population of Abeta40 and Abeta42 peptides. An anti-amyloid effect of siNAs is observed in a wide spectrum of cell lines as well as in primary cortical neurons. Thus targeting BACE with small inhibitory nucleic acids may be beneficial for the treatment of Alzheimer's disease and for future drug design.

APA, Harvard, Vancouver, ISO, and other styles

42

Parsons, R. B., and B. M. Austen. "Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 974–79. http://dx.doi.org/10.1042/bst0350974.

Full text

Abstract:

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

APA, Harvard, Vancouver, ISO, and other styles

43

Espinoza, Daniel O., Anna Potempska, George Merz, Katherine Mack, Pankaj Metha, Julia R. Currie, and David L. Miller. "Roles of β-amyloid converting enzymes BACE-1 and BACE-2 in β-amyloid secretion." Neurobiology of Aging 21 (May 2000): 254. http://dx.doi.org/10.1016/s0197-4580(00)83094-8.

Full text

APA, Harvard, Vancouver, ISO, and other styles

44

Zou, Lin, Zhu Wang, Li Shen, Guo Bin Bao, Tian Wang, Jiu Hong Kang, and Gang Pei. "Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization." Cell Research 17, no. 5 (February 27, 2007): 389–401. http://dx.doi.org/10.1038/cr.2007.5.

Full text

APA, Harvard, Vancouver, ISO, and other styles

45

Keskin, Aylin D., Maja Kekuš, Helmuth Adelsberger, Ulf Neumann, Derya R. Shimshek, Beomjong Song, Benedikt Zott, et al. "BACE inhibition-dependent repair of Alzheimer’s pathophysiology." Proceedings of the National Academy of Sciences 114, no. 32 (July 24, 2017): 8631–36. http://dx.doi.org/10.1073/pnas.1708106114.

Full text

Abstract:

Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.

APA, Harvard, Vancouver, ISO, and other styles

46

Lopez, Susanna, Claudio Del Percio, Gianluigi Forloni, Angelisa Frasca, Wilhelmus Drinkenburg, Roberta Lizio, Giuseppe Noce, et al. "Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study." International Journal of Molecular Sciences 21, no. 23 (November 28, 2020): 9072. http://dx.doi.org/10.3390/ijms21239072.

Full text

Abstract:

Objective. In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer’s disease (AD) amyloid neuropathology as compared to wild type (WT) mice. Methods. Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested. Results. Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition (p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor). Conclusions. The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers.

APA, Harvard, Vancouver, ISO, and other styles

47

Webb, Robin L., and M. Paul Murphy. "β-Secretases, Alzheimer’s Disease, and Down Syndrome." Current Gerontology and Geriatrics Research 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/362839.

Full text

Abstract:

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer’s disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of theβ-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein byβ-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβpeptide. Increased amounts of APP in the DS brain result in increased amounts of Aβand extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS.

APA, Harvard, Vancouver, ISO, and other styles

48

McGraw, Gary. "Silver Bullet Talks with Becky Bace." IEEE Security & Privacy Magazine 5, no. 3 (May 2007): 6–9. http://dx.doi.org/10.1109/msp.2007.70.

Full text

APA, Harvard, Vancouver, ISO, and other styles

49

Mullard, Asher. "BACE inhibitor bust in Alzheimer trial." Nature Reviews Drug Discovery 16, no. 3 (March 2017): 155. http://dx.doi.org/10.1038/nrd.2017.43.

Full text

APA, Harvard, Vancouver, ISO, and other styles

50

Mullard, Asher. "BACE failures lower AD expectations, again." Nature Reviews Drug Discovery 17, no. 6 (June 2018): 385. http://dx.doi.org/10.1038/nrd.2018.94.

Full text

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'BACE'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles