Journal articles: 'Beta-secretase'

1

Liao, Francesca-Fang, Ruishan Wang, and Edwards A. Park. "Repression of Alzheimer's beta-Secretase." Aging 5, no. 11 (October 26, 2013): 789–90. http://dx.doi.org/10.18632/aging.100612.

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Kuentzel, S. L., S. M. Ali, R. A. Altman, B. D. Greenberg, and T. J. Raub. "The Alzheimer β-amyloid protein precursor/protease nexin-II is cleaved by secretase in a trans-Golgi secretory compartment in human neuroglioma cells." Biochemical Journal 295, no. 2 (October 15, 1993): 367–78. http://dx.doi.org/10.1042/bj2950367.

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Alzheimer beta-amyloid protein precursor (beta APP) is expressed endogenously and abundantly by human neuroglioma (H4) cells. Its secretory processing has been shown to involve discrete proteolysis within the beta A4 region, thus preventing beta-amyloid formation, by an enzyme which has been referred to as ‘beta APP secretase’. This cleavage results in secretion of a soluble N-terminal 135 kDa protein and retention of an integral membrane C-terminal fragment within the cell. The membrane-associated C-terminal fragment is sorted to lysosomes where it undergoes limited degradation. We show here that most newly synthesized beta APP is degraded via a non-lysosomal pathway before maturation in H4 cells, and most mature beta APP is processed predominantly by the so-called secretase. The rapid kinetics of appearance/disappearance of a cleaved 135 kDa protein within a microsomal fraction and the slow accumulation of this form in the extracellular medium indicated that secretase cleaves beta APP in an intracellular compartment. Low-temperature block (20 degrees C) was used to demonstrate that beta APP is cleaved within a late Golgi compartment after sulphation which occurs in the trans-Golgi network (TGN). This is consistent with (1) the immunolocalization of most of the beta APP within a Golgi compartment that reacts with wheat germ agglutinin, (2) the fact that less than 1.5% of the total mature full-length beta APP is present at the plasma membrane and (3) subcellular fractionation studies which showed that the mature full-length and intracellular cleaved beta APPs co-sediment with a membrane fraction that is slightly more dense than the plasma membrane. This study provides evidence that most of the beta APP secretase in H4 cells is intracellular, and confirms that the resulting C-terminal fragment is delivered to lysosomes immediately after cleavage. These results are discussed with regard to the possibility that mature full-length beta APP escapes secretase cleavage and is delivered directly from the TGN to the lysosome without passing through the plasma membrane. Either pathway will result in the generation of amyloidogenic fragments.

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Venugopal, Chitra, Christina Demos, K. Jagannatha Rao, Miguel Pappolla, and Kumar Sambamurti. "Beta-Secretase: Structure, Function, and Evolution." CNS & Neurological Disorders - Drug Targets 7, no. 3 (June 1, 2008): 278–94. http://dx.doi.org/10.2174/187152708784936626.

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Vassar, Robert. "PL-04-01: Targeting beta-secretase." Alzheimer's & Dementia 9 (July 2013): P677. http://dx.doi.org/10.1016/j.jalz.2013.04.332.

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Chang, Wan‐Pin, Deborah Downs, Xiang‐Ping Huang, Huining Da, Kar‐Ming Fung, and Jordan Tang. "Amyloid‐beta reduction by memapsin 2 (beta‐secretase) immunization." FASEB Journal 21, no. 12 (May 10, 2007): 3184–96. http://dx.doi.org/10.1096/fj.06-7993com.

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Nunan, Janelle, and David H. Small. "Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease." Essays in Biochemistry 38 (October 1, 2002): 37–49. http://dx.doi.org/10.1042/bse0380037.

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The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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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.

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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.

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Ghosh, Arun, Nagaswamy Kumaragurubaran, Ling Hong, Gerald Koelsh, and Jordan Tang. "Memapsin 2 (Beta-Secretase) Inhibitors: Drug Development." Current Alzheimer Research 5, no. 2 (April 1, 2008): 121–31. http://dx.doi.org/10.2174/156720508783954730.

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Farah, MohamedH, and Carolyn Tallon. "Beta secretase activity in peripheral nerve regeneration." Neural Regeneration Research 12, no. 10 (2017): 1565. http://dx.doi.org/10.4103/1673-5374.217319.

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Cole, Sarah L., and Robert Vassar. "The Alzheimer's disease Beta-secretase enzyme, BACE1." Molecular Neurodegeneration 2, no. 1 (2007): 22. http://dx.doi.org/10.1186/1750-1326-2-22.

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11

Naushad, Mehjabeen, Siva Sundara Kumar Durairajan, Amal Kanti Bera, Sanjib Senapati, and Min Li. "Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease." Planta Medica 85, no. 17 (October 16, 2019): 1316–25. http://dx.doi.org/10.1055/a-1019-9819.

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AbstractAlzheimerʼs disease is a neurodegenerative disease that leads to irreversible neuronal damage. Senile plaques, composed of amyloid beta peptide, is the principal abnormal characteristic of the disease. Among the factors involved, the secretase enzymes, namely, α secretase, beta-site amyloid precursor protein-cleaving enzyme, β secretase, and γ secretase, hold consequential importance. Beta-site amyloid precursor protein-cleaving enzyme 1 is considered to be the rate-limiting factor in the production of amyloid beta peptide. Research supporting the concept of inhibition of beta-site amyloid precursor protein-cleaving enzyme activity as one of the effective therapeutic targets in the mitigation of Alzheimerʼs disease is well accepted. The identification of natural compounds, such as β-amyloid precursor protein-selective beta-site amyloid precursor protein-cleaving enzyme inhibitors, and the idea of compartmentalisation of the beta-site amyloid precursor protein-cleaving enzyme 1 action have caused a dire need to closely examine the natural compounds and their effectiveness in the disease mitigation. Many natural compounds have been reported to effectively modulate beta-site amyloid precursor protein-cleaving enzyme 1. At lower doses, compounds like 2,2′,4′-trihydroxychalcone acid, quercetin, and myricetin have been shown to effectively reduce beta-site amyloid precursor protein-cleaving enzyme 1 activity. The currently used five drugs that are marketed and used for the management of Alzheimerʼs disease have an increased risk of toxicity and restricted therapeutic efficiency, hence, the search for new anti-Alzheimerʼs disease drugs is of primary concern. A variety of natural compounds having pure pharmacological moieties showing multitargeting activity and others exhibiting specific beta-site amyloid precursor protein-cleaving enzyme 1 inhibition as discussed below have superior biosafety. Many of these compounds, which are isolated from medicinal herbs and marine flora, have been long used for the treatment of various ailments since ancient times in the Chinese and Ayurvedic medical systems. The aim of this article is to review the available data on the selected natural compounds, giving emphasis to the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 activity as a mode of Alzheimerʼs disease treatment.

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12

Carter, Chris. "Alzheimer's Disease: APP, Gamma Secretase, APOE, CLU, CR1, PICALM, ABCA7, BIN1, CD2AP, CD33, EPHA1, and MS4A2, and Their Relationships with Herpes Simplex,C. Pneumoniae, Other Suspect Pathogens, and the Immune System." International Journal of Alzheimer's Disease 2011 (2011): 1–34. http://dx.doi.org/10.4061/2011/501862.

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Alzheimer's disease susceptibility genes, APP and gamma-secretase, are involved in the herpes simplex life cycle, and that of other suspect pathogens (C. pneumoniae,H. pylori,C. neoformans,B. burgdorferri,P. gingivalis) or immune defence. Such pathogens promote beta-amyloid deposition andtauphosphorylation and may thus be causative agents, whose effects are conditioned by genes. The antimicrobial effects of beta-amyloid, the localisation of APP/gamma-secretase in immunocompetent dendritic cells, and gamma secretase cleavage of numerous pathogen receptors suggest that this network is concerned with pathogen disposal, effects which may be abrogated by the presence of beta-amyloid autoantibodies in the elderly. These autoantibodies, as well as those to nerve growth factor andtau, also observed in Alzheimer's disease, may well be antibodies to pathogens, due to homology between human autoantigens and pathogen proteins. NGF ortauantibodies promote beta-amyloid deposition, neurofibrillary tangles, or cholinergic neuronal loss, and, with other autoantibodies, such as anti-ATPase, are potential agents of destruction, whose formation is dictated by sequence homology between pathogen and human proteins, and thus by pathogen strain and human genes. Pathogen elimination in the ageing population and removal of culpable autoantibodies might reduce the incidence and offer hope for a cure in this affliction.

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Nisha, Chaluveelaveedu Murleedharan, Ashwini Kumar, Prateek Nair, Nityasha Gupta, Chitrangda Silakari, Timir Tripathi, and Awanish Kumar. "Molecular Docking and In Silico ADMET Study Reveals Acylguanidine 7a as a Potential Inhibitor of β-Secretase." Advances in Bioinformatics 2016 (April 10, 2016): 1–6. http://dx.doi.org/10.1155/2016/9258578.

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Amyloidogenic pathway in Alzheimer’s disease (AD) involves breakdown of APP by β-secretase followed by γ-secretase and results in formation of amyloid beta plaque. β-secretase has been a promising target for developing novel anti-Alzheimer drugs. To test different molecules for this purpose, test ligands like acylguanidine 7a, rosiglitazone, pioglitazone, and tartaric acid were docked against our target protein β-secretase enzyme retrieved from Protein Data Bank, considering MK-8931 (phase III trial, Merck) as the positive control. Docking revealed that, with respect to their free binding energy, acylguanidine 7a has the lowest binding energy followed by MK-8931 and pioglitazone and binds significantly to β-secretase. In silico ADMET predictions revealed that except tartaric acid all other compounds had minimal toxic effects and had good absorption as well as solubility characteristics. These compounds may serve as potential lead compound for developing new anti-Alzheimer drug.

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Yu, Zhipeng, Huizhuo Ji, Juntong Shen, Ruotong Kan, Wenzhu Zhao, Jianrong Li, Long Ding, and Jingbo Liu. "Identification and molecular docking study of fish roe-derived peptides as potent BACE 1, AChE, and BChE inhibitors." Food & Function 11, no. 7 (2020): 6643–51. http://dx.doi.org/10.1039/d0fo00971g.

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15

Wang, Hualong, Xia Liu, Shengdi Chen, and Keqiang Ye. "Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer’s disease." Proceedings of the National Academy of Sciences 115, no. 52 (December 10, 2018): E12427—E12434. http://dx.doi.org/10.1073/pnas.1815915115.

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Alzheimer’s disease (AD) neuropathological hallmarks include senile plaques with aggregated amyloid beta as a major component, neurofibrillary tangles (NFT) containing truncated and hyperphosphorylated Tau, extensive neuronal loss, and chronic neuroinflammation. However, the key molecular mechanism that dominates the pathogenesis of AD remains elusive for AD. Here we show that the C/EBPβ/δ-secretase axis is activated in an age-dependent manner in different brain regions of the 3×Tg AD mouse model, elevating δ-secretase–truncated APP and Tau proteolytic truncates and promoting senile plaques and NFT formation in the brain, associated with gradual neuronal loss and chronic neuroinflammation. Depletion of inflammatory cytokine-regulated transcription factor C/EBPβ from 3×Tg mice represses APP, Tau, and δ-secretase expression, which subsequently inhibits APP and Tau cleavage, leading to mitigation of AD pathologies. Knockout of δ-secretase from 3×Tg mice strongly blunts AD pathogenesis. Consequently, inactivation of the C/EBPβ/δ-secretase axis ameliorates cognitive dysfunctions in 3×Tg mice by blocking APP and Tau expression and their pathological fragmentation. Thus, our findings support the notion that C/EBPβ/δ-secretase axis plays a crucial role in AD pathogenesis.

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Owens, Lauren, Joshua Bracewell, Alexandre Benedetto, Neil Dawson, Christopher Gaffney, and Edward Parkin. "BACE1 Overexpression Reduces SH-SY5Y Cell Viability Through a Mechanism Distinct from Amyloid-β Peptide Accumulation: Beta Prime-Mediated Competitive Depletion of sAβPPα." Journal of Alzheimer's Disease 86, no. 3 (April 5, 2022): 1201–20. http://dx.doi.org/10.3233/jad-215457.

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Background: The Alzheimer’s disease (AD)-associated amyloid-beta protein precursor (AβPP) can be cleaved by β-site AβPP cleaving enzyme 1 (BACE1) and the γ-secretase complex to yield neurotoxic amyloid-β (Aβ) peptides. However, AβPP can also be cleaved in a ‘non-amyloidogenic’ manner either by α-secretase to produce soluble AβPP alpha (sAβPPα) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated ‘beta prime’ activity yielding soluble AβPP beta prime (sAβPPβ’). Objective: To determine whether sAβPPα depletion, as opposed to Aβ peptide accumulation, contributes to cytotoxicity in AD-relevant SH-SY5Y neuroblastoma cell models. Methods: AβPP proteolysis was characterized by immunoblotting in mock-, wild-type AβPP (wtAβPP)-, BACE1-, and Swedish mutant AβPP (SweAβPP)-transfected cells. AβPP beta prime cleavage was confirmed through secretase inhibitor studies and C-terminal fragment analysis. The roles of sAβPPα and sAβPPβ’ in cell viability were confirmed by overexpression studies. Results: Despite producing enhanced Aβ peptide levels, wtAβPP- and SweAβPP-transfected cells did not exhibit reduced viability whereas BACE1-transfected cells did. sAβPPα generation in SH-SY5Y-BACE1 cells was virtually ablated in lieu of BACE1-mediated sAβPPβ’ production. sAβPPα overexpression in SH-SY5Y-BACE1 cells restored viability whereas sAβPPβ’ overexpression decreased viability further. The anti-AβPP 6E10 antibody was shown to cross-react with sAβPPβ’. Conclusion: sAβPPα depletion and/or sAβPPβ’ accumulation, but not elevated Aβ peptide levels, represent the cytotoxic mechanism following BACE1 overexpression in SH-SY5Y cells. These data support the novel concept that competitive sAβPPα depletion by BACE1 beta prime activity might contribute to AD. The cross-reactivity of 6E10 with AβPPβ’also questions whether previous studies assessing sAβPPα as a biomarker using this antibody should be revisited.

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Semighini, Evandro Pizeta. "In SilicoDesign of Beta-Secretase Inhibitors in Alzheimer's Disease." Chemical Biology & Drug Design 86, no. 3 (December 28, 2014): 284–90. http://dx.doi.org/10.1111/cbdd.12492.

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Sidera, Christina, Richard Parsons, and Brian Austen. "Post-translational processing of beta-secretase in Alzheimer's disease." PROTEOMICS 5, no. 6 (April 2005): 1533–43. http://dx.doi.org/10.1002/pmic.200401185.

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Holsinger, R. M. Damian, Nelleke Goense, John Bohorquez, and Padraig Strappe. "Splice variants of the Alzheimer’s disease beta-secretase, BACE1." neurogenetics 14, no. 1 (November 11, 2012): 1–9. http://dx.doi.org/10.1007/s10048-012-0348-3.

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20

Citron, Martin O. "PL-02-02: Beta-secretase as a therapeutic target." Alzheimer's & Dementia 2 (July 2006): S23. http://dx.doi.org/10.1016/j.jalz.2006.05.071.

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Alasmari, Fawaz, Musaad A. Alshammari, Abdullah F. Alasmari, Wael A. Alanazi, and Khalid Alhazzani. "Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism." BioMed Research International 2018 (October 25, 2018): 1–8. http://dx.doi.org/10.1155/2018/3087475.

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Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer’s disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.

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Watanabe, Hikari, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Taisuke Tomita, and Eugene Futai. "Specific Mutations in Aph1 Cause γ-Secretase Activation." International Journal of Molecular Sciences 23, no. 1 (January 3, 2022): 507. http://dx.doi.org/10.3390/ijms23010507.

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Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity.

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Lee, Yoon-Jee, Jong-Sung Park, A.-Ryeong Gwoan, Mark Mattson, and Dong-Gyu Jo. "P4-320: Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease." Alzheimer's & Dementia 8, no. 4S_Part_21 (July 2012): S771. http://dx.doi.org/10.1016/j.jalz.2013.08.101.

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Zacchetti, Daniele, Barbara Bettegazzi, Alessandra Consonni, Romina Macco, Ilaria Pelizzoni, Franca Codazzi, and Fabio Grohovaz. "P3-352: Beta-secretase modulation and amyloid-beta production in rat brain primary cultures." Alzheimer's & Dementia 4 (July 2008): T625. http://dx.doi.org/10.1016/j.jalz.2008.05.1922.

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Ghosh, Arun, Geoffrey Bilcer, Lin Hong, Gerald Koelsch, and Jordan Tang. "Memapsin 2 (Beta-Secretase) Inhibitor Drug, between Fantasy and Reality." Current Alzheimer Research 4, no. 4 (September 1, 2007): 418–22. http://dx.doi.org/10.2174/156720507781788864.

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Austen, Brian M., and Christina Sidera. "P4-370 Palmitoylation of beta-secretase is abolished by lovastatin." Neurobiology of Aging 25 (July 2004): S580. http://dx.doi.org/10.1016/s0197-4580(04)81928-6.

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Vassar, Robert. "BACE1, the Alzheimer's beta-secretase enzyme, in health and disease." Molecular Neurodegeneration 7, Suppl 1 (2012): L3. http://dx.doi.org/10.1186/1750-1326-7-s1-l3.

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Ali, Meer Asif, Sugunakar Vuree, Himshikha Goud, Tajamul Hussain, Anuraj Nayarisseri, and Sanjeev Kumar Singh. "Identification of High-affinity Small Molecules Targeting Gamma Secretase for the Treatment of Alzheimer’s Disease." Current Topics in Medicinal Chemistry 19, no. 13 (August 27, 2019): 1173–87. http://dx.doi.org/10.2174/1568026619666190617155326.

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Background: Alzheimers Disease (AD) is a neurodegenerative disease which is characterized by the deposition of amyloid plaques in the brain- a concept supported by most of the researchers worldwide. The main component of the plaques being amyloid-beta (Aβ42) results from the sequential cleavage of Amyloid precursor protein (APP) by beta and gamma secretase. This present study intends to inhibit the formation of amyloid plaques by blocking the action of gamma secretase protein with Inhibitors (GSI). Methods: A number of Gamma Secretase Inhibitors (GSI) were targeted to the protein by molecular docking. The inhibitor having the best affinity was used as a subject for further virtual screening methods to obtain similar compounds. The generated compounds were docked again at the same docking site on the protein to find a compound with higher affinity to inhibit the protein. The highlights of virtually screened compound consisted of Pharmacophore Mapping of the docking site. These steps were followed by comparative assessments for both the compounds, obtained from the two aforesaid docking studies, which included interaction energy descriptors, ADMET profiling and PreADMET evaluations. Results: 111 GSI classified as azepines, sulfonamides and peptide isosteres were used in the study. By molecular docking an amorpholino-amide, compound (22), was identified to be the high affinity compound GSI along with its better interaction profiles.The virtually screened pubchem compound AKOS001083915 (CID:24462213) shows the best affinity with gamma secretase. Collective Pharmacophore mapping (H bonds, electrostatic profile, binding pattern and solvent accesibility) shows a stable interaction. The resulting ADMETand Descriptor values were nearly equivalent. Conclusion: These compounds identified herein hold a potential as Gamma Secretase inhibitors.According to PreADMET values the compound AKOS001083915 is effective and specific to the target protein. Its BOILED-egg plot analysis infers the compound permeable to blood brain barrier.Comparative study for both the compounds resulted in having nearly equivalent properties. These compounds have the capacity to inhibit the protein which is indirectly responsible for the formation of amyloid plaques and can be further put to in vitro pharmacokinetic and dynamic studies.

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Gijsen, Harrie J. M., and Marc Mercken. "-Secretase Modulators: Can We Combine Potency with Safety?" International Journal of Alzheimer's Disease 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/295207.

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-Secretase modulation has been proposed as a potential disease modifying anti-Alzheimer’s approach. -Secretase modulators (GSMs) cause a product shift from the longer amyloid-beta (Aβ) peptide isoforms to shorter, more soluble, and less amyloidogenic isoforms, without inhibiting APP or Notch proteolytic processing. As such, modulating -secretase may avoid some of the adverse effects observed with -secretase inhibitors. Since the termination of the GSM tarenfurbil in 2008 due to negative phase III trial results, a considerable progress has been made towards more potent and better brain penetrable compounds. However, an analysis of their lipophilic efficiency indices indicates that their increased potency can be largely attributed to their increased lipophilicity. The need for early and chronic dosing with GSMs will require high-safety margins. This will be a challenge to achieve with the current, highly lipophilic GSMs. We will demonstrate that by focusing on the drug-like properties of GSMs, a combination of highin vitropotency and reduced lipophilicity can be achieved and does result in better tolerated compounds. The next hurdle will be to translate this knowledge into GSMs which are highly efficacious and safein vivo.

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Lin, X., G. Koelsch, S. Wu, D. Downs, A. Dashti, and J. Tang. "Human aspartic protease memapsin 2 cleaves the beta -secretase site of beta -amyloid precursor protein." Proceedings of the National Academy of Sciences 97, no. 4 (February 15, 2000): 1456–60. http://dx.doi.org/10.1073/pnas.97.4.1456.

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Yao, Yinan, Seong Su Kang, Yiyuan Xia, Zhi-Hao Wang, Xia Liu, Thorsten Muller, Yi E. Sun, and Keqiang Ye. "A delta-secretase-truncated APP fragment activates CEBPB, mediating Alzheimer’s disease pathologies." Brain 144, no. 6 (April 20, 2021): 1833–52. http://dx.doi.org/10.1093/brain/awab062.

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Abstract Amyloid-β precursor protein (APP) is sequentially cleaved by secretases and generates amyloid-β, the major components in senile plaques in Alzheimer’s disease. APP is upregulated in human Alzheimer’s disease brains. However, the molecular mechanism of how APP contributes to Alzheimer’s disease pathogenesis remains incompletely understood. Here we show that truncated APP C586-695 fragment generated by δ-secretase directly binds to CCAAT/enhancer-binding protein beta (CEBPB), an inflammatory transcription factor, and enhances its transcriptional activity, escalating Alzheimer’s disease-related gene expression and pathogenesis. The APP C586-695 fragment, but not full-length APP, strongly associates with CEBPB and elicits its nuclear translocation and augments the transcriptional activities on APP itself, MAPT (microtubule-associated protein tau), δ-secretase and inflammatory cytokine mRNA expression, finally triggering Alzheimer’s disease pathology and cognitive disorder in a viral overexpression mouse model. Blockade of δ-secretase cleavage of APP by mutating the cleavage sites reduces its stimulatory effect on CEBPB, alleviating amyloid pathology and cognitive dysfunctions. Clearance of APP C586-695 from 5xFAD mice by antibody administration mitigates Alzheimer’s disease pathologies and restores cognitive functions. Thus, in addition to the sequestration of amyloid-β, APP implicates in Alzheimer’s disease pathology by activating CEBPB upon δ-secretase cleavage.

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Toh, Wei Hong, Pei Zhi Cheryl Chia, Mohammed Iqbal Hossain, and Paul A. Gleeson. "GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Aβ production." Molecular Biology of the Cell 29, no. 2 (January 15, 2018): 191–208. http://dx.doi.org/10.1091/mbc.e17-05-0270.

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The diversion of the β-secretase BACE1 from the endo-lysosomal pathway to recycling endosomes is important in the regulation of amyloid beta production. Here we define BACE1 transport from early to recycling endosomes and identify essential roles for the SNX4-mediated, signal-independent pathway and for a signal-mediated, GGA1-dependent pathway.

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Cai, Zhiyou, Chuanling Wang, Wenbo He, and Yi Chen. "Berberine Alleviates Amyloid-Beta Pathology in the Brain of APP/PS1 Transgenic Mice via Inhibiting β/γ-Secretases Activity and Enhancing α-Secretases." Current Alzheimer Research 15, no. 11 (September 7, 2018): 1045–52. http://dx.doi.org/10.2174/1567205015666180702105740.

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Background: Berberine (BBR) has neuroprotective effects on many brain diseases, including Alzheimer’s disease (AD). Amyloid -beta (Aβ) senile plaque is the most classical pathological hallmarks of AD. Aβ produces from a sequential cleavage by β-secretase (beta-site amyloid precursor protein cleaving enzyme 1, BACE1) and γ -secretase. The aim of our work was to investigate whether the neuroprotective effects of BBR on AD is related to inhibiting Aβ pathology. Method: The cognitive function of mice was assessed by the Morris water maze (MWM) test. The Aβ levels were determined by enzyme linked immunosorbent assay; the expression of APP, sAPPα, ADAM10 and ADAM17, sAPPβ and BACE1 was detected by Western blotting; and the activity of γ -secretase complex (NCT, PS1, Aph-1α and Pen-2) was determined by Western blotting and immunohistochemistry. Results: BBR improved learning and memory deficits of APP/PS1 mice. BBR decreased Aβ levels in the hippocampus of APP/PS1 mice. BACE1 and sAPP -β levels in the BBR-treated groups were significantly reduced in the hippocampus of AD mice. BBR markedly decreased the expression of PS1, Aph-1α and Pen-2, but had no effect on NCT. The levels of sAPPα, ADAM10 and ADAM17 in the hippocampus of BBR-treated mice significantly increased, compared with the control ones (P<0.05). Conclusion: BBR inhibits the activity of β/γ-secretases, enhances α-secretases, and lowers the Aβ level in the hippocampus of AD mice, and improves Alzheimer’s-like cognitive impairment.

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Parkin, Edward T., Jessica E. Hammond, Lauren Owens, and Matthew D. Hodges. "The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein." PLOS ONE 17, no. 1 (January 13, 2022): e0255715. http://dx.doi.org/10.1371/journal.pone.0255715.

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The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer’s disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the ’amyloidogenic’ proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the ’non-amyloidogenic’ pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β–secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer’s disease.

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Lee, Joo-Hee, Na-Hyun Ahn, Su-Bin Choi, Youngeun Kwon, and Seung-Hoon Yang. "Natural Products Targeting Amyloid Beta in Alzheimer’s Disease." International Journal of Molecular Sciences 22, no. 5 (February 26, 2021): 2341. http://dx.doi.org/10.3390/ijms22052341.

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.

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Chakravarthy and Veedu. "BACE1 Inhibition Using 2’-OMePS Steric Blocking Antisense Oligonucleotides." Genes 10, no. 9 (September 12, 2019): 705. http://dx.doi.org/10.3390/genes10090705.

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Amyloid beta-peptide is produced by the cleavage of amyloid precursor protein by two secretases, a β-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and a γ-secretase. It has been hypothesised that partial inhibition of BACE1 in individuals with a high risk of developing Alzheimer’s disease may be beneficial in preventing cognitive decline. In this study, we report the development of a novel antisense oligonucleotide (AO) that could efficiently downregulate the BACE1 transcript and partially inhibit BACE1 protein. We designed and synthesised a range of 2’-OMethyl-modified antisense oligonucleotides with a phosphorothioate backbone across various exons of the BACE1 transcript, of which AO2, targeting exon 2, efficiently downregulated BACE1 RNA expression by 90%. The sequence of AO2 was later synthesised with a phosphorodiamidate morpholino chemistry, which was found to be not as efficient at downregulating BACE1 expression as the 2’-OMethyl antisense oligonucleotides with a phosphorothioate backbone variant. AO2 also reduced BACE1 protein levels by 45%. In line with our results, we firmly believe that AO2 could be used as a potential preventative therapeutic strategy for Alzheimer’s disease.

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Yu, Haung, Ana Maria Cuervo, Asok Kumar, Lars Tjernberg, Mark R. Farmery, Corrinne M. Peterhoff, and Ralph A. Nixon. "P1-163 Autophagic vacuoles contain high beta and gamma secretase activities." Neurobiology of Aging 25 (July 2004): S142. http://dx.doi.org/10.1016/s0197-4580(04)80476-7.

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Rossner, Steffen, Christine Lange-Dohna, Ulrike Zeitschel, and J. Regino Perez-Polo. "Alzheimer's disease beta-secretase BACE1 is not a neuron-specific enzyme." Journal of Neurochemistry 92, no. 2 (January 2005): 226–34. http://dx.doi.org/10.1111/j.1471-4159.2004.02857.x.

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McConlogue, Lisa Claire, David A. Agard, Nobuyuki Ota, and Gwen Tatsuno. "Functional analysis of beta-secretase using mutagenesis and structural homology modeling." Neurobiology of Aging 21 (May 2000): 278. http://dx.doi.org/10.1016/s0197-4580(00)83203-0.

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Dovey, H. F., V. John, J. P. Anderson, L. Z. Chen, P. De Saint Andrieu, L. Y. Fang, S. B. Freedman, et al. "Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain." Journal of Neurochemistry 76, no. 1 (April 22, 2009): 173–81. http://dx.doi.org/10.1046/j.1471-4159.2001.00012.x.

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Züchner, Thole, J. Regino Perez-Polo, and Reinhard Schliebs. "Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor signaling." Journal of Neuroscience Research 77, no. 2 (May 5, 2004): 250–57. http://dx.doi.org/10.1002/jnr.20152.

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Kashima, Yusei, and Mitsuo Miyazawa. "Structure-activity Relationships for Bergenin Analogues as ^|^beta;-Secretase (BACE1) Inhibitors." Journal of Oleo Science 62, no. 6 (2013): 391–401. http://dx.doi.org/10.5650/jos.62.391.

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Knopman, David S. "Lowering of Amyloid-Beta by β-Secretase Inhibitors — Some Informative Failures." New England Journal of Medicine 380, no. 15 (April 11, 2019): 1476–78. http://dx.doi.org/10.1056/nejme1903193.

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Tang, Jordan J. N. "F1-01-04: Beta-secretase as target for amyloid-reduction therapy." Alzheimer's & Dementia 5, no. 4S_Part_3 (July 2009): P74. http://dx.doi.org/10.1016/j.jalz.2009.05.177.

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Bittner, Heiko J., Ramon Guixà-González, and Peter W. Hildebrand. "Structural basis for the interaction of the beta-secretase with copper." Biochimica et Biophysica Acta (BBA) - Biomembranes 1860, no. 5 (May 2018): 1105–13. http://dx.doi.org/10.1016/j.bbamem.2018.01.019.

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Innocenti, Riccardo, Elena Lenci, Gloria Menchi, Alberto Pupi, and Andrea Trabocchi. "Design and synthesis of bicyclic acetals as Beta Secretase (BACE1) inhibitors." Bioorganic & Medicinal Chemistry 25, no. 19 (October 2017): 5077–83. http://dx.doi.org/10.1016/j.bmc.2017.03.030.

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Mok, Ngai Y., James Chadwick, Katherine A. B. Davey, Nigel M. Hooper, A. Peter Johnson, and Colin W. G. Fishwick. "P2-482: De novo design of cellular active beta-secretase inhibitors." Alzheimer's & Dementia 4 (July 2008): T515—T516. http://dx.doi.org/10.1016/j.jalz.2008.05.1560.

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Bush, A. I., W. H. Pettingell, M. D. Paradis, and R. E. Tanzi. "Modulation of A beta adhesiveness and secretase site cleavage by zinc." Journal of Biological Chemistry 269, no. 16 (April 1994): 12152–58. http://dx.doi.org/10.1016/s0021-9258(17)32694-7.

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Farzan, M., C. E. Schnitzler, N. Vasilieva, D. Leung, and H. Choe. "BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein." Proceedings of the National Academy of Sciences 97, no. 17 (August 8, 2000): 9712–17. http://dx.doi.org/10.1073/pnas.160115697.

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Robshaw, Ashley, Kevin Atchison, Claude Ambroise, Charles Nolan, Kathleen Wood, Cathleen Gonzales, Christine Oborski, Feng Pan, Eva Hajos-Korcsok, and David Riddell. "P2-394: Characterization of beta-amyloid 1-40 across species following treatment with beta-secretase inhibitors." Alzheimer's & Dementia 9 (July 2013): P502. http://dx.doi.org/10.1016/j.jalz.2013.05.1043.

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Journal articles on the topic 'Beta-secretase'

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