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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Review Article

BACE-1 Inhibitors Targeting Alzheimer's Disease

Author(s): Kadja Luana Chagas Monteiro, Marcone Gomes dos Santos Alcântara, Nathalia Monteiro Lins Freire, Esaú Marques Brandão, Vanessa Lima do Nascimento, Líbni Maísa dos Santos Viana, Thiago Mendonça de Aquino and Edeildo Ferreira da Silva-Júnior*

Volume 20, Issue 3, 2023

Published on: 03 July, 2023

Page: [131 - 148] Pages: 18

DOI: 10.2174/1567205020666230612155953

Price: $65

Abstract

The accumulation of amyloid-β (Aβ) is the main event related to Alzheimer's disease (AD) progression. Over the years, several disease-modulating approaches have been reported, but without clinical success. The amyloid cascade hypothesis evolved and proposed essential targets such as tau protein aggregation and modulation of β-secretase (β-site amyloid precursor protein cleaving enzyme 1 - BACE-1) and γ-secretase proteases. BACE-1 cuts the amyloid precursor protein (APP) to release the C99 fragment, giving rise to several Aβ peptide species during the subsequent γ-secretase cleavage. In this way, BACE-1 has emerged as a clinically validated and attractive target in medicinal chemistry, as it plays a crucial role in the rate of Aβ generation. In this review, we report the main results of candidates in clinical trials such as E2609, MK8931, and AZD-3293, in addition to highlighting the pharmacokinetic and pharmacodynamic-related effects of the inhibitors already reported. The current status of developing new peptidomimetic, non-peptidomimetic, naturally occurring, and other class inhibitors are demonstrated, considering their main limitations and lessons learned. The goal is to provide a broad and complete approach to the subject, exploring new chemical classes and perspectives.

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[1]
2020 Alzheimer’s disease facts and figures. Alzheimers Dement 2020; 16(3): 391-460.
[http://dx.doi.org/10.1002/alz.12068]
[2]
Matsunaga S, Kishi T, Nomura I, et al. The efficacy and safety of memantine for the treatment of Alzheimer’s disease. Expert Opin Drug Saf 2018; 17(10): 1053-61.
[http://dx.doi.org/10.1080/14740338.2018.1524870] [PMID: 30222469]
[3]
Ricciarelli R, Fedele E. The amyloid cascade hypothesis in Alzheimer’s Disease: It’s time to change our mind. Curr Neuropharmacol 2017; 15(6): 926-35.
[PMID: 28093977]
[4]
Sherman MY, Goldberg AL. Cellular defenses against unfolded proteins: A cell biologist thinks about neurodegenerative diseases. Neuron 2001; 29(1): 15-32.
[http://dx.doi.org/10.1016/S0896-6273(01)00177-5] [PMID: 11182078]
[5]
Wang W, Nema S, Teagarden D. Protein aggregation—Pathways and influencing factors. Int J Pharm 2010; 390(2): 89-99.
[http://dx.doi.org/10.1016/j.ijpharm.2010.02.025] [PMID: 20188160]
[6]
Guo T, Hobbs D. Development of BACE1 inhibitors for Alzheimer’s disease. Curr Med Chem 2006; 13(15): 1811-29.
[http://dx.doi.org/10.2174/092986706777452489] [PMID: 16787223]
[7]
Nunan J, Small DH. Regulation of APP cleavage by α-, β- and γ-secretases. FEBS Lett 2000; 483(1): 6-10.
[http://dx.doi.org/10.1016/S0014-5793(00)02076-7] [PMID: 11033346]
[8]
Dingwall C. Spotlight on BACE: The secretases as targets for treatment in Alzheimer disease. J Clin Invest 2001; 108(9): 1243-6.
[http://dx.doi.org/10.1172/JCI14402] [PMID: 11696563]
[9]
Näslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline. JAMA 2000; 283(12): 1571-7.
[http://dx.doi.org/10.1001/jama.283.12.1571] [PMID: 10735393]
[10]
Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nat Genet 1992; 1(5): 345-7.
[http://dx.doi.org/10.1038/ng0892-345] [PMID: 1302033]
[11]
Citron M, Vigo-Pelfrey C, Teplow DB, et al. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci 1994; 91(25): 11993-7.
[http://dx.doi.org/10.1073/pnas.91.25.11993] [PMID: 7991571]
[12]
Head E, Lott IT. Down syndrome and beta-amyloid deposition. Curr Opin Neurol 2004; 17(2): 95-100.
[http://dx.doi.org/10.1097/00019052-200404000-00003] [PMID: 15021233]
[13]
Viola KL, Klein WL. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol 2015; 129(2): 183-206.
[http://dx.doi.org/10.1007/s00401-015-1386-3] [PMID: 25604547]
[14]
He Y, Zheng MM, Ma Y, et al. Soluble oligomers and fibrillar species of amyloid β-peptide differentially affect cognitive functions and hippocampal inflammatory response. Biochem Biophys Res Commun 2012; 429(3-4): 125-30.
[http://dx.doi.org/10.1016/j.bbrc.2012.10.129] [PMID: 23146634]
[15]
Dobrowolska Zakaria JA, Vassar RJ. A promising, novel, and unique BACE 1 inhibitor emerges in the quest to prevent Alzheimer’s disease. EMBO Mol Med 2018; 10(11): e9717.
[http://dx.doi.org/10.15252/emmm.201809717] [PMID: 30322841]
[16]
Reiss AB, Arain HA, Stecker MM, Siegart NM, Kasselman LJ. Amyloid toxicity in Alzheimer’s disease. Rev Neurosci 2018; 29(6): 613-27.
[http://dx.doi.org/10.1515/revneuro-2017-0063] [PMID: 29447116]
[17]
Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 2010; 6(3): 131-44.
[http://dx.doi.org/10.1038/nrneurol.2010.4] [PMID: 20157306]
[18]
Bennett BD, Babu-Khan S, Loeloff R, et al. Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem 2000; 275(27): 20647-51.
[http://dx.doi.org/10.1074/jbc.M002688200] [PMID: 10749877]
[19]
Walter J. Control of amyloid-β-peptide generation by subcellular trafficking of the β-amyloid precursor protein and β-secretase. Neurodegener Dis 2006; 3(4-5): 247-54.
[http://dx.doi.org/10.1159/000095263] [PMID: 17047364]
[20]
Haniu M, Denis P, Young Y, et al. Characterization of Alzheimer’s β -secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem 2000; 275(28): 21099-106.
[http://dx.doi.org/10.1074/jbc.M002095200] [PMID: 10887202]
[21]
Shi XP, Chen E, Yin KC, et al. The pro domain of β-secretase does not confer strict zymogen-like properties but does assist proper folding of the protease domain. J Biol Chem 2001; 276(13): 10366-73.
[http://dx.doi.org/10.1074/jbc.M009200200] [PMID: 11266439]
[22]
Hu B, Xiong B, Qiu B, et al. Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to? -secretase. Acta Pharmacol Sin 2006; 27(12): 1586-93.
[http://dx.doi.org/10.1111/j.1745-7254.2006.00432.x] [PMID: 17112413]
[23]
Rombouts FJR, Alexander R, Cleiren E, et al. Fragment binding to β-Secretase 1 without catalytic aspartate interactions identified via orthogonal screening approaches. ACS Omega 2017; 2(2): 685-97.
[http://dx.doi.org/10.1021/acsomega.6b00482] [PMID: 28626832]
[24]
Citron M. Emerging Alzheimer’s disease therapies: Inhibition of β-secretase. Neurobiol Aging 2002; 23(6): 1017-22.
[http://dx.doi.org/10.1016/S0197-4580(02)00122-7] [PMID: 12470797]
[25]
Xu Y, Li M, Greenblatt H, et al. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations. Acta Crystallogr D Biol Crystallogr 2012; 68(1): 13-25.
[http://dx.doi.org/10.1107/S0907444911047251] [PMID: 22194329]
[26]
Westmeyer GG, Willem M, Lichtenthaler SF, et al. Dimerization of β-site β-amyloid precursor protein-cleaving enzyme. J Biol Chem 2004; 279(51): 53205-12.
[http://dx.doi.org/10.1074/jbc.M410378200] [PMID: 15485862]
[27]
Di Pietro O, Juárez-Jiménez J, Muñoz-Torrero D, Laughton CA, Luque FJ. Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors. PLoS One 2017; 12(5): e0177683.
[http://dx.doi.org/10.1371/journal.pone.0177683] [PMID: 28505196]
[28]
Fischer F, Molinari M, Bodendorf U, Paganetti P. The disulphide bonds in the catalytic domain of BACE are critical but not essential for amyloid precursor protein processing activity. J Neurochem 2002; 80(6): 1079-88.
[http://dx.doi.org/10.1046/j.0022-3042.2002.00806.x] [PMID: 11953458]
[29]
De Strooper B, Vassar R, Golde T. The secretases: Enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010; 6(2): 99-107.
[http://dx.doi.org/10.1038/nrneurol.2009.218] [PMID: 20139999]
[30]
Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s Disease. N Engl J Med 2018; 378(18): 1691-703.
[http://dx.doi.org/10.1056/NEJMoa1706441] [PMID: 29719179]
[31]
Moussa-Pacha NM, Abdin SM, Omar HA, Alniss H, Al-Tel TH. BACE1 inhibitors: Current status and future directions in treating Alzheimer’s disease. Med Res Rev 2020; 40(1): 339-84.
[http://dx.doi.org/10.1002/med.21622] [PMID: 31347728]
[32]
Zimmer JA, Shcherbinin S, Devous MD, Bragg SM, Selzler KJ, Wessels AM, et al. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease. Alzheimers Dement 2021; 7(1): e12123.
[33]
Piton M, Hirtz C, Desmetz C, et al. Alzheimer’s Disease: Advances in drug development. J Alzheimers Dis 2018; 65(1): 3-13.
[http://dx.doi.org/10.3233/JAD-180145] [PMID: 30040716]
[34]
Kumar D, Ganeshpurkar A, Kumar D, Modi G, Gupta SK, Singh SK. Secretase inhibitors for the treatment of Alzheimer’s disease: Long road ahead. Eur J Med Chem 2018; 148: 436-52.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.035] [PMID: 29477076]
[35]
Novak G, Streffer JR, Timmers M, et al. Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer’s disease spectrum patients: A randomized, double-blind, placebo-controlled study and a two-period extension study. Alzheimers Res Ther 2020; 12(1): 58.
[http://dx.doi.org/10.1186/s13195-020-00614-5] [PMID: 32410694]
[36]
Dash C, Kulkarni A, Dunn B, Rao M. Aspartic peptidase inhibitors: Implications in drug development. Crit Rev Biochem Mol Biol 2003; 38(2): 89-119.
[http://dx.doi.org/10.1080/713609213] [PMID: 12749695]
[37]
Ghosh AK, Osswald HL. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease. Chem Soc Rev 2014; 43(19): 6765-813.
[http://dx.doi.org/10.1039/C3CS60460H] [PMID: 24691405]
[38]
Nantermet PG, Rajapakse HA, Stanton MG, et al. Evolution of tertiary carbinamine BACE-1 inhibitors: Abeta reduction in rhesus CSF upon oral dosing. ChemMedChem 2009; 4(1): 37-40.
[http://dx.doi.org/10.1002/cmdc.200800308] [PMID: 19085994]
[39]
Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000; 290(5489): 150-3.
[40]
Hong L, Turner RT III, Koelsch G, Shin D, Ghosh AK, Tang J. Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3. Biochemistry 2002; 41(36): 10963-7.
[http://dx.doi.org/10.1021/bi026232n] [PMID: 12206667]
[41]
Ghosh AK, Lei H, Devasamudram T, Liu C, Tang JJNBG. United States Patent US7335632, 2008.
[42]
Ghosh AK, Kumaragurubaran N, Hong L, et al. Design, synthesis and X-ray structure of protein-ligand complexes: Important insight into selectivity of memapsin 2 (β-secretase) inhibitors. J Am Chem Soc 2006; 128(16): 5310-1.
[http://dx.doi.org/10.1021/ja058636j] [PMID: 16620080]
[43]
Ghosh A, Lei H, Devasamudram T, Lui C, Tang J BG. Amino-containing compounds which inhibit memapsin 2 beta-secretase activity and methods of use thereof. WO2006034296, 2006.
[44]
Ghosh AK, Lei H, Devasamudram T, Liu C, Tang J BG. Bicyclic compounds which inhibit beta-secretase activity and methods of use thereof. WO2006034277, 2006.
[45]
Coburn CA, Stachel SJ, Li YM, et al. Identification of a small molecule nonpeptide active site β-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. J Med Chem 2004; 47(25): 6117-9.
[http://dx.doi.org/10.1021/jm049388p] [PMID: 15566281]
[46]
Stachel SJ, Coburn CA, Steele TG, et al. Structure-based design of potent and selective cell-permeable inhibitors of human β-secretase (BACE-1). J Med Chem 2004; 47(26): 6447-50.
[http://dx.doi.org/10.1021/jm049379g] [PMID: 15588077]
[47]
Stachel SJ, Coburn CA, Steele TG, et al. Conformationally biased P3 amide replacements of β-secretase inhibitors. Bioorg Med Chem Lett 2006; 16(3): 641-4.
[http://dx.doi.org/10.1016/j.bmcl.2005.10.032] [PMID: 16263281]
[48]
Clarke B, Demont E, Dingwall C, et al. BACE-1 inhibitors Part 1: Identification of novel hydroxy ethylamines (HEAs). Bioorg Med Chem Lett 2008; 18(3): 1011-6.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.017] [PMID: 18171614]
[49]
Clarke B, Demont E, Dingwall C, et al. BACE-1 inhibitors part 2: Identification of hydroxy ethylamines (HEAs) with reduced peptidic character. Bioorg Med Chem Lett 2008; 18(3): 1017-21.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.019] [PMID: 18166458]
[50]
Charrier N, Clarke B, Demont E, et al. Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent. Bioorg Med Chem Lett 2009; 19(13): 3669-73.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.150] [PMID: 19477642]
[51]
Charrier N, Clarke B, Cutler L, et al. Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics. Bioorg Med Chem Lett 2009; 19(13): 3674-8.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.149] [PMID: 19406640]
[52]
Charrier N, Clarke B, Cutler L, et al. Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics. Bioorg Med Chem Lett 2009; 19(13): 3664-8.
[http://dx.doi.org/10.1016/j.bmcl.2009.03.165] [PMID: 19428244]
[53]
Ghosh AK, Kumaragurubaran N, Hong L, et al. Potent memapsin 2 (β-secretase) inhibitors: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorg Med Chem Lett 2008; 18(3): 1031-6.
[http://dx.doi.org/10.1016/j.bmcl.2007.12.028] [PMID: 18180160]
[54]
Freskos JN, Fobian YM, Benson TE, et al. Design of potent inhibitors of human β-secretase. Part 2. Bioorg Med Chem Lett 2007; 17(1): 78-81.
[http://dx.doi.org/10.1016/j.bmcl.2006.09.091] [PMID: 17049233]
[55]
Maillard MC, Hom RK, Benson TE, et al. Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase. J Med Chem 2007; 50(4): 776-81.
[http://dx.doi.org/10.1021/jm061242y] [PMID: 17300163]
[56]
Hu B, Fan KY, Bridges K, et al. Synthesis and SAR of bis-statine based peptides as BACE 1 inhibitors. Bioorg Med Chem Lett 2004; 14(13): 3457-60.
[http://dx.doi.org/10.1016/j.bmcl.2004.04.068] [PMID: 15177452]
[57]
Kimura T, Shuto D, Kasai S, et al. KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine. Bioorg Med Chem Lett 2004; 14(6): 1527-31.
[http://dx.doi.org/10.1016/j.bmcl.2003.12.088] [PMID: 15006396]
[58]
Kimura T, Hamada Y, Stochaj M, et al. Design and synthesis of potent β-secretase (BACE1) inhibitors with P 1 ´ carboxylic acid bioisosteres. Bioorg Med Chem Lett 2006; 16(9): 2380-6.
[http://dx.doi.org/10.1016/j.bmcl.2006.01.108] [PMID: 16481167]
[59]
Hamada Y, Igawa N, Ikari H, et al. β-Secretase inhibitors: Modification at the P4 position and improvement of inhibitory activity in cultured cells. Bioorg Med Chem Lett 2006; 16(16): 4354-9.
[http://dx.doi.org/10.1016/j.bmcl.2006.05.046] [PMID: 16757166]
[60]
Hamada Y, Abdel-Rahman H, Yamani A, et al. BACE1 inhibitors: Optimization by replacing the P 1 ´ residue with non-acidic moiety. Bioorg Med Chem Lett 2008; 18(5): 1649-53.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.058] [PMID: 18249539]
[61]
Coburn CA, Stachel SJ, Jones KG, et al. BACE-1 inhibition by a series of ψ[CH2NH] reduced amide isosteres. Bioorg Med Chem Lett 2006; 16(14): 3635-8.
[http://dx.doi.org/10.1016/j.bmcl.2006.04.076] [PMID: 16690314]
[62]
Ghosh AK, Venkateswara Rao K, Yadav ND, et al. Structure-based design of highly selective β-secretase inhibitors: Synthesis, biological evaluation, and protein-ligand X-ray crystal structure. J Med Chem 2012; 55(21): 9195-207.
[http://dx.doi.org/10.1021/jm3008823] [PMID: 22954357]
[63]
Jeon SY, Bae K, Seong YH, Song KS. Green tea catechins as a BACE1 (β-Secretase) inhibitor. Bioorg Med Chem Lett 2003; 13(22): 3905-8.
[http://dx.doi.org/10.1016/j.bmcl.2003.09.018] [PMID: 14592472]
[64]
Jeon SY, Kwon SH, Seong YH, et al. β-secretase (BACE1)- inhibiting stilbenoids from Smilax Rhizoma. Phytomedicine 2007; 14(6): 403-8.
[http://dx.doi.org/10.1016/j.phymed.2006.09.003] [PMID: 17084604]
[65]
Ahn J, Um M, Choi W, Kim S, Ha T. Protective effects of Glycyrrhiza uralensis Fisch. on the cognitive deficits caused by β-amyloid peptide 25-35 in young mice. Biogerontology 2006; 7(4): 239-47.
[http://dx.doi.org/10.1007/s10522-006-9023-0] [PMID: 16821116]
[66]
Tse AKW, Wan CK, Zhu GY, et al. Magnolol suppresses NF-κB activation and NF-κB regulated gene expression through inhibition of IkappaB kinase activation. Mol Immunol 2007; 44(10): 2647-58.
[http://dx.doi.org/10.1016/j.molimm.2006.12.004] [PMID: 17240450]
[67]
Chen SC, Chang YL, Wang DL, Cheng JJ. Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells. Br J Pharmacol 2006; 148(2): 226-32.
[http://dx.doi.org/10.1038/sj.bjp.0706647] [PMID: 16520748]
[68]
Lee J, Jung E, Park J, et al. Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling. Planta Med 2005; 71(4): 338-43.
[http://dx.doi.org/10.1055/s-2005-864100] [PMID: 15856410]
[69]
Lee EB, Zhang B, Liu K, et al. BACE overexpression alters the subcellular processing of APP and inhibits Aβ deposition in vivo. J Cell Biol 2005; 168(2): 291-302.
[http://dx.doi.org/10.1083/jcb.200407070] [PMID: 15642747]
[70]
Park J, Lee J, Jung E, et al. In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp. Eur J Pharmacol 2004; 496(1-3): 189-95.
[http://dx.doi.org/10.1016/j.ejphar.2004.05.047] [PMID: 15288590]
[71]
Liou KT, Shen YC, Chen CF, Tsao CM, Tsai SK. Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain Res 2003; 992(2): 159-66.
[http://dx.doi.org/10.1016/j.brainres.2003.08.026] [PMID: 14625055]
[72]
Haraguchi H, Ishikawa H, Shirataki N, Fukuda A. Antiperoxidative activity of neolignans from Magnolia obovata. J Pharm Pharmacol 2011; 49(2): 209-12.
[http://dx.doi.org/10.1111/j.2042-7158.1997.tb06781.x] [PMID: 9055197]
[73]
Lin YR, Chen HH, Ko CH, Chan MH. Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage. Eur J Pharmacol 2006; 537(1-3): 64-9.
[http://dx.doi.org/10.1016/j.ejphar.2006.03.035] [PMID: 16631734]
[74]
Tsai T, Westly J, Lee T, Chen C, Wang L. Effects of honokiol and magnolol on acetylcholine release from rat hippocampal slices. Planta Med 1995; 61(5): 477-9.
[http://dx.doi.org/10.1055/s-2006-958142] [PMID: 7480213]
[75]
Fukuyama Y, Otoshi Y, Miyoshi K, et al. Neurotrophic sesquiterpene-neolignans from magnolia obovata: Structure and neurotrophic activity. Tetrahedron 1992; 48(3): 377-92.
[http://dx.doi.org/10.1016/S0040-4020(01)89002-5]
[76]
Yamazaki R, Sugatani J, Fujii I, et al. Development of a novel method for determination of acetyl-CoA:1-alkyl-sn-glycero-3-phosphocholine acetyltransferase activity and its application to screening for acetyltransferase inhibitors. Biochem Pharmacol 1994; 47(6): 995-1006.
[http://dx.doi.org/10.1016/0006-2952(94)90410-3] [PMID: 8147919]
[77]
Lee JW, Lee YK, Lee BJ, et al. Inhibitory effect of ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on memory impairment and neuronal toxicity induced by beta-amyloid. Pharmacol Biochem Behav 2010; 95(1): 31-40.
[http://dx.doi.org/10.1016/j.pbb.2009.12.003] [PMID: 20004682]
[78]
Nie HZ, Shi S, Lukas RJ, Zhao WJ, Sun YN, Yin M. Activation of α7 nicotinic receptor affects APP processing by regulating secretase activity in SH-EP1-α7 nAChR-hAPP695 cells. Brain Res 2010; 1356: 112-20.
[http://dx.doi.org/10.1016/j.brainres.2010.07.110] [PMID: 20708605]
[79]
Paris D, Beaulieu-Abdelahad D, Bachmeier C, et al. Anatabine lowers Alzheimer’s Aβ production in vitro and in vivo. Eur J Pharmacol 2011; 670(2-3): 384-91.
[http://dx.doi.org/10.1016/j.ejphar.2011.09.019] [PMID: 21958873]
[80]
Marumoto S, Miyazawa M. β-secretase inhibitory effects of furanocoumarins from the root of Angelica dahurica. Phytother Res 2010; 24(4): 510-3.
[http://dx.doi.org/10.1002/ptr.2967] [PMID: 20041416]
[81]
Marumoto S, Miyazawa M. Structure-activity relationships for naturally occurring coumarins as β-secretase inhibitor. Bioorg Med Chem 2012; 20(2): 784-8.
[http://dx.doi.org/10.1016/j.bmc.2011.12.002] [PMID: 22222157]
[82]
Rafiquzzaman SM, Min Lee J, Ahmed R, Lee JH, Kim JM, Kong IS. Characterisation of the hypoglycaemic activity of glycoprotein purified from the edible brown seaweed, Undaria pinnatifida. Int J Food Sci Technol 2015; 50(1): 143-50.
[http://dx.doi.org/10.1111/ijfs.12663]
[83]
Rafiquzzaman SM, Kim EY, Lee JM, et al. Anti-Alzheimers and anti-inflammatory activities of a glycoprotein purified from the edible brown alga Undaria pinnatifida. Food Res Int 2015; 77: 118-24.
[http://dx.doi.org/10.1016/j.foodres.2015.08.021]
[84]
Leirós M, Alonso E, Rateb ME, et al. Gracilins: Spongionella-derived promising compounds for Alzheimer disease. Neuropharmacology 2015; 93: 285-93.
[http://dx.doi.org/10.1016/j.neuropharm.2015.02.015] [PMID: 25724081]
[85]
Nguyen VT, To DC, Tran MH, et al. Isolation of cholinesterase and β-secretase 1 inhibiting compounds from Lycopodiella cernua. Bioorg Med Chem 2015; 23(13): 3126-34.
[http://dx.doi.org/10.1016/j.bmc.2015.04.080] [PMID: 26003344]
[86]
Linhardt RJ, Toida T. Role of glycosaminoglycans in cellular communication. Acc Chem Res 2004; 37(7): 431-8.
[http://dx.doi.org/10.1021/ar030138x] [PMID: 15260505]
[87]
Capila I, Linhardt RJ. Heparin-protein interactions. Angew Chem Int Ed 2002; 41(3): 390-412.
[http://dx.doi.org/10.1002/1521-3773(20020201)41:3<390:AID-ANIE390>3.0.CO;2-B] [PMID: 12491369]
[88]
Omar SH, Scott CJ, Hamlin AS, Obied HK. Biophenols: Enzymes (β-secretase, Cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.). Fitoterapia 2018; 128: 118-29.
[http://dx.doi.org/10.1016/j.fitote.2018.05.011] [PMID: 29772299]
[89]
Qi B, Liu X, Mo T, et al. 3,5-Dimethylorsellinic acid derived meroterpenoids from Penicillium chrysogenum MT-12, an endophytic fungus isolated from Huperzia serrata. J Nat Prod 2017; 80(10): 2699-707.
[http://dx.doi.org/10.1021/acs.jnatprod.7b00438] [PMID: 28960979]
[90]
Qi C, Zhou Q, Gao W, et al. Anti-BACE1 and anti-AchE activities of undescribed spiro-dioxolane-containing meroterpenoids from the endophytic fungus Aspergillus terreus Thom. Phytochemistry 2019; 165: 112041.
[http://dx.doi.org/10.1016/j.phytochem.2019.05.014] [PMID: 31203103]
[91]
Perry NSL, Bollen C, Perry EK, Ballard C. Salvia for dementia therapy: Review of pharmacological activity and pilot tolerability clinical trial. Pharmacol Biochem Behav 2003; 75(3): 651-9.
[http://dx.doi.org/10.1016/S0091-3057(03)00108-4] [PMID: 12895683]
[92]
Perry NSL, Houghton PJ, Theobald A, Jenner P, Perry EK. In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes. J Pharm Pharmacol 2010; 52(7): 895-902.
[http://dx.doi.org/10.1211/0022357001774598] [PMID: 10933142]
[93]
Tildesley NTJ, Kennedy DO, Perry EK, et al. Salvia lavandulaefolia (Spanish Sage) enhances memory in healthy young volunteers. Pharmacol Biochem Behav 2003; 75(3): 669-74.
[http://dx.doi.org/10.1016/S0091-3057(03)00122-9] [PMID: 12895685]
[94]
Savelev SU, Okello EJ, Perry EK. Butyryl- and acetyl-cholinesterase inhibitory activities in essential oils ofSalvia species and their constituents. Phytother Res 2004; 18(4): 315-24.
[http://dx.doi.org/10.1002/ptr.1451] [PMID: 15162368]
[95]
Gürbüz P, Martinez A, Pérez C, Martínez-González L, Göger F. Ayran İ. Potential anti-Alzheimer effects of selected Lamiaceae plants through polypharmacology on glycogen synthase kinase-3β β-secretase, and casein kinase 1δ. Ind Crops Prod 2019; 138: 111431.
[http://dx.doi.org/10.1016/j.indcrop.2019.05.080]
[96]
Liu T, An XN, Liu DL, Wei YJ. A comparison of several second-order algorithms for simultaneous determination of neomangiferin and mangiferin with severe spectral overlapping in Anemarrhenae Rhizoma. Spectrochim Acta A Mol Biomol Spectrosc 2019; 208: 172-8.
[http://dx.doi.org/10.1016/j.saa.2018.09.057] [PMID: 30312844]
[97]
Chu SH, Hu HY, Tan ZW, Chen X, Wang WH, Zhang XY. Effect of qingxin kaiqiao formula and saponin on learning and memory abilities and expression of apoptosis signal transducers Abeta and betaAPP in AD rat brain. Zhongguo Zhongyao Zazhi 2012; 37(19): 2947-50.
[PMID: 23270239]
[98]
Wang HQ, Liu M, Wang L, et al. Identification of a novel BACE1 inhibitor, timosaponin A-III, for treatment of Alzheimer’s disease by a cell extraction and chemogenomics target knowledgebase-guided method. Phytomedicine 2020; 75: 153244.
[http://dx.doi.org/10.1016/j.phymed.2020.153244] [PMID: 32502824]
[99]
Toda T, Sunagawa T, Kanda T, Tagashira M, Shirasawa T, Shimizu T. Apple procyanidins suppress amyloid β -protein aggregation. Biochem Res Int 2011; 2011: 1-8.
[http://dx.doi.org/10.1155/2011/784698] [PMID: 21826271]
[100]
Cheng D, Xi Y, Cao J, Cao D, Ma Y, Jiang W. Protective effect of apple (Ralls) polyphenol extract against aluminum-induced cognitive impairment and oxidative damage in rat. Neurotoxicology 2014; 45: 111-20.
[http://dx.doi.org/10.1016/j.neuro.2014.10.006] [PMID: 25445564]
[101]
El-Hawary SS, Hammam WE, El-Mahdy El-Tantawi M, et al. Apple leaves and their major secondary metabolite phlorizin exhibit distinct neuroprotective activities: Evidence from in vivo and in silico studies. Arab J Chem 2021; 14(6): 103188.
[http://dx.doi.org/10.1016/j.arabjc.2021.103188]
[102]
Ye Q, Qin G, Zhao W. Immunomodulatory sesquiterpene glycosides from Dendrobium nobile. Phytochemistry 2002; 61(8): 885-90.
[http://dx.doi.org/10.1016/S0031-9422(02)00484-3] [PMID: 12453511]
[103]
Hsieh YSY, Chien C, Liao SKS, et al. Structure and bioactivity of the polysaccharides in medicinal plant Dendrobium huoshanense. Bioorg Med Chem 2008; 16(11): 6054-68.
[http://dx.doi.org/10.1016/j.bmc.2008.04.042] [PMID: 18467102]
[104]
Ye LH, Zhang R, Cao J. Screening of β-secretase inhibitors from Dendrobii Caulis by covalently enzyme-immobilized magnetic beads coupled with ultra-high-performance liquid chromatography. J Pharm Biomed Anal 2021; 195: 113845.
[http://dx.doi.org/10.1016/j.jpba.2020.113845] [PMID: 33371968]
[105]
Peters S, Fuchs K, Eickmeier C, et al. Substituted ethane-1,2- diamines for the treatment of alzheimer's disease. WO- 2005113582-A1, 2007.
[106]
Hosen SMZ, Rubayed M, Dash R, et al. Prospecting and structural insight into the binding of novel plant-derived molecules of leea indica as inhibitors of BACE1. Curr Pharm Des 2019; 24(33): 3972-9.
[http://dx.doi.org/10.2174/1381612824666181106111020] [PMID: 30398111]
[107]
Raihan MO, Habib MR, Brishti A, Rahman MM, Saleheen MM, Manna M. Sedative and anxiolytic effects of the methanolic extract of Leea indica (Burm. f.) Merr. leaf. Drug Discov Ther 2011; 5(4): 185-9.
[http://dx.doi.org/10.5582/ddt.2011.v5.4.185] [PMID: 22466299]
[108]
Wong YH, Abdul Kadir H, Ling SK. Bioassay-guided isolation of cytotoxic cycloartane triterpenoid glycosides from the traditionally used medicinal plant Leea indica. Evid Based Complement Alternat Med 2012; 2012: 1-11.
[http://dx.doi.org/10.1155/2012/164689] [PMID: 22203865]
[109]
Zhong Q, Wei B, Wang S, et al. The antioxidant activity of polysaccharides derived from marine organisms: An overview. Mar Drugs 2019; 17(12): 674.
[http://dx.doi.org/10.3390/md17120674] [PMID: 31795427]
[110]
Han Y, Nan S, Fan J, Chen Q, Zhang Y. Inonotus obliquus polysaccharides protect against Alzheimer’s disease by regulating Nrf2 signaling and exerting antioxidative and antiapoptotic effects. Int J Biol Macromol 2019; 131: 769-78.
[http://dx.doi.org/10.1016/j.ijbiomac.2019.03.033] [PMID: 30878614]
[111]
He Y, Xu W, Qin Y. Structural characterization and neuroprotective effect of a polysaccharide from Corydalis yanhusuo. Int J Biol Macromol 2020; 157: 759-68.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.01.180] [PMID: 31987950]
[112]
Cavalli A, Bolognesi ML, Mìnarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem 2008; 51(3): 347-72.
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[113]
Prati F, Bottegoni G, Bolognesi ML, Cavalli A. BACE-1 inhibitors: From recent single-target molecules to multitarget compounds for Alzheimer’s Disease. J Med Chem 2018; 61(3): 619-37.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00393] [PMID: 28749667]
[114]
Ghosh AK, Brindisi M, Yen YC, et al. Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand. Bioorg Med Chem Lett 2015; 25(3): 668-72.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.087] [PMID: 25537272]
[115]
Verma A, Kumar Waiker D, Bhardwaj B, Saraf P, Shrivastava SK. The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer’s disease. Bioorg Chem 2022; 119: 105562.
[http://dx.doi.org/10.1016/j.bioorg.2021.105562] [PMID: 34952243]
[116]
Tarazi H, Odeh RA, Al-Qawasmeh R, Yousef IA, Voelter W, Al-Tel TH. Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer’s disease. Eur J Med Chem 2017; 125: 1213-24.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.021] [PMID: 27871037]
[117]
Dorababu A. Promising heterocycle-based scaffolds in recent (2019-2021) anti-Alzheimer’s drug design and discovery. Eur J Pharmacol 2022; 920: 174847.
[http://dx.doi.org/10.1016/j.ejphar.2022.174847] [PMID: 35218718]
[118]
Iraji A, Firuzi O, Khoshneviszadeh M, Nadri H, Edraki N, Miri R. Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer’s disease. Bioorg Chem 2018; 77: 223-35.
[http://dx.doi.org/10.1016/j.bioorg.2018.01.017] [PMID: 29367079]
[119]
Ramrao SP, Verma A, Waiker DK, Tripathi PN, Shrivastava SK. Design, synthesis, and evaluation of some novel biphenyl imidazole derivatives for the treatment of Alzheimer’s disease. J Mol Struct 2021; 1246: 131152.
[http://dx.doi.org/10.1016/j.molstruc.2021.131152]
[120]
Choubey PK, Tripathi A, Sharma P, Shrivastava SK. Design, synthesis, and multitargeted profiling of N-benzylpyrrolidine derivatives for the treatment of Alzheimer’s disease. Bioorg Med Chem 2020; 28(22): 115721.
[http://dx.doi.org/10.1016/j.bmc.2020.115721] [PMID: 33007563]
[121]
Gabr MT, Abdel-Raziq MS. Structure-based design, synthesis, and evaluation of structurally rigid donepezil analogues as dual AChE and BACE-1 inhibitors. Bioorg Med Chem Lett 2018; 28(17): 2910-3.
[http://dx.doi.org/10.1016/j.bmcl.2018.07.019] [PMID: 30017317]
[122]
Sharma P, Tripathi A, Tripathi PN, et al. Design and development of multitarget-directed N-Benzylpiperidine analogs as potential candidates for the treatment of Alzheimer’s disease. Eur J Med Chem 2019; 167: 510-24.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.030] [PMID: 30784883]
[123]
Ferreira JPS, Albuquerque HMT, Cardoso SM, Silva AMS, Silva VLM. Dual-target compounds for Alzheimer’s disease: Natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR). Eur J Med Chem 2021; 221: 113492.
[http://dx.doi.org/10.1016/j.ejmech.2021.113492] [PMID: 33984802]
[124]
Sharma P, Tripathi A, Tripathi PN, Singh SS, Singh SP, Shrivastava SK. Novel molecular hybrids of N -Benzylpiperidine and 1,3,4-Oxadiazole as multitargeted therapeutics to treat Alzheimer’s Disease. ACS Chem Neurosci 2019; 10(10): 4361-84.
[http://dx.doi.org/10.1021/acschemneuro.9b00430] [PMID: 31491074]
[125]
Tripathi A, Choubey PK, Sharma P, et al. Design and development of molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles as potential multifunctional agents to treat Alzheimer’s disease. Eur J Med Chem 2019; 183: 111707.
[http://dx.doi.org/10.1016/j.ejmech.2019.111707] [PMID: 31561043]
[126]
Choubey PK, Tripathi A, Tripathi MK, Seth A, Shrivastava SK. Design, synthesis, and evaluation of N-benzylpyrrolidine and 1,3,4-oxadiazole as multitargeted hybrids for the treatment of Alzheimer’s disease. Bioorg Chem 2021; 111: 104922.
[http://dx.doi.org/10.1016/j.bioorg.2021.104922] [PMID: 33945941]
[127]
Tripathi A, Choubey PK, Sharma P, Seth A, Saraf P, Shrivastava SK. Design, synthesis, and biological evaluation of ferulic acid based 1,3,4-oxadiazole hybrids as multifunctional therapeutics for the treatment of Alzheimer’s disease. Bioorg Chem 2020; 95: 103506.
[http://dx.doi.org/10.1016/j.bioorg.2019.103506] [PMID: 31887472]
[128]
Franklin PX, Pillai AD, Rathod PD, et al. 2-Amino-5-thiazolyl motif: A novel scaffold for designing anti-inflammatory agents of diverse structures. Eur J Med Chem 2008; 43(1): 129-34.
[http://dx.doi.org/10.1016/j.ejmech.2007.02.008] [PMID: 17467123]
[129]
Hsiao CC, Rombouts F, Gijsen HJM. New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorg Med Chem Lett 2019; 29(6): 761-77.
[http://dx.doi.org/10.1016/j.bmcl.2018.12.049] [PMID: 30709653]
[130]
Sagar SR, Singh DP, Panchal NB, et al. Thiazolyl-thiadiazines as beta site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitors and anti-inflammatory agents: multitarget-directed ligands for the efficient management of Alzheimer’s disease. ACS Chem Neurosci 2018; 9(7): 1663-79.
[http://dx.doi.org/10.1021/acschemneuro.8b00063] [PMID: 29697965]
[131]
Sagar SR, Singh DP, Das RD, et al. Pharmacological investigation of quinoxaline-bisthiazoles as multitarget-directed ligands for the treatment of Alzheimer’s disease. Bioorg Chem 2019; 89: 102992.
[http://dx.doi.org/10.1016/j.bioorg.2019.102992] [PMID: 31174042]
[132]
Al-Tel TH, Semreen MH, Al-Qawasmeh RA, et al. Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer’s drug leads. J Med Chem 2011; 54(24): 8373-85.
[http://dx.doi.org/10.1021/jm201181f] [PMID: 22044119]
[133]
Al-Tel TH, Al-Qawasmeh RA, Schmidt MF, et al. Rational design and synthesis of potent dibenzazepine motifs as β-secretase inhibitors. J Med Chem 2009; 52(20): 6484-8.
[http://dx.doi.org/10.1021/jm9008482] [PMID: 19788239]
[134]
Li HM, Yu SP, Fan TY, et al. Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity. Drug Dev Res 2020; 81(2): 206-14.
[http://dx.doi.org/10.1002/ddr.21585] [PMID: 31397505]
[135]
Qu L, Ji L, Wang C, et al. Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer’s disease. Eur J Med Chem 2021; 219: 113441.
[http://dx.doi.org/10.1016/j.ejmech.2021.113441] [PMID: 33862517]
[136]
Tok F. Sağlık BN, Özkay Y, Kaplancıklı ZA, Koçyiğit- Kaymakçıoğlu B. Design, synthesis, biological activity evaluation and in silico studies of new nicotinohydrazide derivatives as multi-targeted inhibitors for Alzheimer’s disease. J Mol Struct 2022; 1265: 133441.
[http://dx.doi.org/10.1016/j.molstruc.2022.133441]
[137]
Jagtap AD, Kondekar NB, Hung PY, et al. 4-Substituted 2-amino-3,4-dihydroquinazolines with a 3-hairpin turn side chain as novel inhibitors of BACE-1. Bioorg Chem 2020; 95: 103135.
[http://dx.doi.org/10.1016/j.bioorg.2019.103135] [PMID: 31923631]
[138]
Winneroski LL, Erickson JA, Green SJ, et al. Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints. Bioorg Med Chem 2020; 28(1): 115194.
[http://dx.doi.org/10.1016/j.bmc.2019.115194] [PMID: 31786008]
[139]
Baxter EW, Reitz AB. BACE inhibitors for the treatment of Alzheimer’s Disease. PA 19477-0776, 2005.
[http://dx.doi.org/10.1016/S0065-7743(05)40003-2]
[140]
Olson RE, Marcin LR. Secretase inhibitors and modulators for the treatment of alzheimer’s disease author links open overlay panel Annual Reports in Medicinal Chemistry. Amsterdam: Elsevier 2007.
[141]
Evin G, Barakat A, Masters CL. BACE: Therapeutic target and potential biomarker for Alzheimer’s disease. Int J Biochem Cell Biol 2010; 42(12): 1923-6.
[http://dx.doi.org/10.1016/j.biocel.2010.08.017] [PMID: 20817005]
[142]
Stamford A, Strickland C. Inhibitors of BACE for treating Alzheimer’s disease: A fragment-based drug discovery story. Curr Opin Chem Biol 2013; 17(3): 320-8.
[http://dx.doi.org/10.1016/j.cbpa.2013.04.016] [PMID: 23683349]
[143]
Ugbaja SC, Lawal IA, Kumalo HM, Lawal MM. Alzheimer’s Disease and β-secretase inhibition: An Update with a focus on computer-aided inhibitor design. Curr Drug Targets 2022; 23(3): 266-85.
[http://dx.doi.org/10.2174/1389450122666210809100050] [PMID: 34370634]
[144]
Liu S, Fu R, Cheng X, Chen SP, Zhou LH. Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE). BMC Struct Biol 2012; 12(1): 21.
[http://dx.doi.org/10.1186/1472-6807-12-21] [PMID: 22925713]
[145]
Kocak A, Erol I, Yildiz M, Can H. Computational insights into the protonation states of catalytic dyad in BACE1-acyl guanidine based inhibitor complex. J Mol Graph Model 2016; 70: 226-35.
[http://dx.doi.org/10.1016/j.jmgm.2016.10.013] [PMID: 27770745]
[146]
Barman A, Prabhakar R. Protonation states of the catalytic dyad of β-secretase (BACE1) in the presence of chemically diverse inhibitors: A molecular docking study. J Chem Inf Model 2012; 52(5): 1275-87.
[http://dx.doi.org/10.1021/ci200611t] [PMID: 22545704]
[147]
Domínguez JL, Christopeit T, Villaverde MC, et al. Effect of the protonation state of the titratable residues on the inhibitor affinity to BACE-1. Biochemistry 2010; 49(34): 7255-63.
[http://dx.doi.org/10.1021/bi100637n] [PMID: 20687525]
[148]
Abdul-Hay SO, Sahara T, McBride M, Kang D, Leissring MA. Identification of BACE2 as an avid ß-amyloid-degrading protease. Mol Neurodegener 2012; 7(1): 46.
[http://dx.doi.org/10.1186/1750-1326-7-46] [PMID: 22986058]
[149]
Hernández-Rodríguez M, Correa-Basurto J, Gutiérrez A, Vitorica J, Rosales-Hernández MC. Asp32 and Asp228 determine the selective inhibition of BACE1 as shown by docking and molecular dynamics simulations. Eur J Med Chem 2016; 124: 1142-54.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.028] [PMID: 27639619]
[150]
Mouton-Liger F, Dumurgier J, Cognat E, et al. CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer’s disease. Alzheimers Res Ther 2020; 12(1): 88.
[http://dx.doi.org/10.1186/s13195-020-00655-w] [PMID: 32690068]
[151]
Ben Halima S, Mishra S, Raja KMP, et al. Specific inhibition of β-Secretase processing of the alzheimer disease amyloid precursor protein. Cell Rep 2016; 14(9): 2127-41.
[http://dx.doi.org/10.1016/j.celrep.2016.01.076] [PMID: 26923602]
[152]
Esparza TJ, Zhao H, Cirrito JR, et al. Amyloid-β oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 2013; 73(1): 104-19.
[http://dx.doi.org/10.1002/ana.23748] [PMID: 23225543]
[153]
De Strooper B. Lessons from a failed γ-secretase Alzheimer trial. Cell 2014; 159(4): 721-6.
[http://dx.doi.org/10.1016/j.cell.2014.10.016] [PMID: 25417150]

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