β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.

Biomedical Research Center University Hospital Hradec Kralove Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence in Brno Hradec Kralove Czech Republic

Zobrazit více v PubMed

Selkoe D.J. The molecular pathology of Alzheimer’s disease. Neuron. 1991;6(4):487–498. doi: 10.1016/0896-6273(91)90052-2. PubMed DOI

Román G.C., Kalaria R.N. Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol. Aging. 2006;27(12):1769–1785. doi: 10.1016/j.neurobiolaging.2005.10.004. PubMed DOI

Vardy E.R.L.C., Catto A.J., Hooper N.M. Proteolytic mechanisms in amyloid-β metabolism: therapeutic implications for Alzheimer’s disease. Trends Mol. Med. 2005;11(10):464–472. doi: 10.1016/j.molmed.2005.08.004. PubMed DOI

Tanzi R.E., Gusella J.F., Watkins P.C., Bruns G.A., St George-Hyslop P., Van Keuren M.L., Patterson D., Pagan S., Kurnit D.M., Neve R.L. Amyloid beta protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science. 1987;235(4791):880–884. doi: 10.1126/science.2949367. PubMed DOI

Goldgaber D., Lerman M.I., McBride O.W., Saffiotti U., Gajdusek D.C. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science. 1987;235(4791):877–880. doi: 10.1126/science.3810169. PubMed DOI

König G., Mönning U., Czech C., Prior R., Banati R., Schreiter-Gasser U., Bauer J., Masters C.L., Beyreuther K. Identification and differential expression of a novel alternative splice isoform of the beta A4 amyloid precursor protein (APP) mRNA in leukocytes and brain microglial cells. J. Biol. Chem. 1992;267(15):10804–10809. PubMed

Norstrom E. Metabolic processing of the amyloid precursor protein -- new pieces of the Alzheimer’s puzzle. Discov. Med. 2017;23(127):269–276. PubMed

Sathya M., Premkumar P., Karthick C., Moorthi P., Jayachandran K.S., Anusuyadevi M. BACE1 in Alzheimer’s disease. Clin. Chim. Acta. 2012;414:171–178. doi: 10.1016/j.cca.2012.08.013. PubMed DOI

He X., Zhu G., Koelsch G., Rodgers K.K., Zhang X.C., Tang J. Biochemical and structural characterization of the interaction of memapsin 2 (β-secretase) cytosolic domain with the VHS domain of GGA proteins. Biochemistry. 2003;42(42):12174–12180. doi: 10.1021/bi035199h. PubMed DOI

Waldron E., Heilig C., Schweitzer A., Nadella N., Jaeger S., Martin A.M., Weggen S., Brix K., Pietrzik C.U. LRP1 modulates APP trafficking along early compartments of the secretory pathway. Neurobiol. Dis. 2008;31(2):188–197. doi: 10.1016/j.nbd.2008.04.006. PubMed DOI

Cole S.L., Vassar R. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. J. Biol. Chem. 2008;283(44):29621–29625. doi: 10.1074/jbc.R800015200. PubMed DOI PMC

Deng Y., Wang Z., Wang R., Zhang X., Zhang S., Wu Y., Staufenbiel M., Cai F., Song W. Amyloid-β protein (Aβ) Glu11 is the major β-secretase site of β-site amyloid-β precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 2013;37(12):1962–1969. doi: 10.1111/ejn.12235. PubMed DOI

Zhang S., Wang Z., Cai F., Zhang M., Wu Y., Zhang J., Song W. BACE1 Cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis. J. Neurosci. 2017;37(29):6915–6925. doi: 10.1523/JNEUROSCI.0340-17.2017. PubMed DOI PMC

Haass C., Lemere C.A., Capell A., Citron M., Seubert P., Schenk D., Lannfelt L., Selkoe D.J. The Swedish mutation causes early-onset Alzheimer’s disease by β-secretase cleavage within the secretory pathway. Nat. Med. 1995;1(12):1291–1296. doi: 10.1038/nm1295-1291. PubMed DOI

Mullan M., Crawford F., Axelman K., Houlden H., Lilius L., Winblad B., Lannfelt L. A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Nat. Genet. 1992;1(5):345–347. doi: 10.1038/ng0892-345. PubMed DOI

Cole S.L., Vassar R. The Alzheimer’s disease β-secretase enzyme, BACE1. Mol. Neurodegener. 2007;2:22. doi: 10.1186/1750-1326-2-22. PubMed DOI PMC

Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R., Scheres S.H.W., Shi Y. Three-dimensional structure of human γ-secretase. Nature. 2014;512(7513):166–170. doi: 10.1038/nature13567. PubMed DOI PMC

Zhang X., Li Y., Xu H., Zhang Y.W. The γ-secretase complex: from structure to function. Front. Cell. Neurosci. 2014;8:427. doi: 10.3389/fncel.2014.00427. PubMed DOI PMC

Somavarapu A.K., Kepp K.P. Membrane dynamics of γ-secretase provides a molecular basis for β-Amyloid binding and processing. ACS Chem. Neurosci. 2017;8(11):2424–2436. doi: 10.1021/acschemneuro.7b00208. PubMed DOI

Morimoto A., Irie K., Murakami K., Masuda Y., Ohigashi H., Nagao M., Fukuda H., Shimizu T., Shirasawa T. Analysis of the secondary structure of β-amyloid (Abeta42) fibrils by systematic proline replacement. J. Biol. Chem. 2004;279(50):52781–52788. doi: 10.1074/jbc.M406262200. PubMed DOI

Koelsch G. BACE1 Function and inhibition: Implications of intervention in the amyloid pathway of Alzheimer’s Disease pathology. Molecules. 2017;22(10):1723. doi: 10.3390/molecules22101723. PubMed DOI PMC

Tcw J., Goate A.M. Genetics of β-Amyloid precursor protein in Alzheimer’s disease. Cold Spring Harb. Perspect. Med. 2017;7(6):a024539. doi: 10.1101/cshperspect.a024539. PubMed DOI PMC

Maloney J.A., Bainbridge T., Gustafson A., Zhang S., Kyauk R., Steiner P., van der Brug M., Liu Y., Ernst J.A., Watts R.J., Atwal J.K. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J. Biol. Chem. 2014;289(45):30990–31000. doi: 10.1074/jbc.M114.589069. PubMed DOI PMC

Tanzi R.E. The genetics of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012;2(10):a006296. doi: 10.1101/cshperspect.a006296. PubMed DOI PMC

Jonsson T., Atwal J.K., Steinberg S., Snaedal J., Jonsson P.V., Bjornsson S., Stefansson H., Sulem P., Gudbjartsson D., Maloney J., Hoyte K., Gustafson A., Liu Y., Lu Y., Bhangale T., Graham R.R., Huttenlocher J., Bjornsdottir G., Andreassen O.A., Jönsson E.G., Palotie A., Behrens T.W., Magnusson O.T., Kong A., Thorsteinsdottir U., Watts R.J., Stefansson K. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488(7409):96–99. doi: 10.1038/nature11283. PubMed DOI

Hussain I., Powell D., Howlett D.R., Tew D.G., Meek T.D., Chapman C., Gloger I.S., Murphy K.E., Southan C.D., Ryan D.M., Smith T.S., Simmons D.L., Walsh F.S., Dingwall C., Christie G. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. 1999;14(6):419–427. doi: 10.1006/mcne.1999.0811. PubMed DOI

Sinha S., Anderson J.P., Barbour R., Basi G.S., Caccavello R., Davis D., Doan M., Dovey H.F., Frigon N., Hong J., Jacobson-Croak K., Jewett N., Keim P., Knops J., Lieberburg I., Power M., Tan H., Tatsuno G., Tung J., Schenk D., Seubert P., Suomensaari S.M., Wang S., Walker D., Zhao J., McConlogue L., John V. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature. 1999;402(6761):537–540. doi: 10.1038/990114. PubMed DOI

Vassar R., Bennett B.D., Babu-Khan S., Kahn S., Mendiaz E.A., Denis P., Teplow D.B., Ross S., Amarante P., Loeloff R., Luo Y., Fisher S., Fuller J., Edenson S., Lile J., Jarosinski M.A., Biere A.L., Curran E., Burgess T., Louis J.C., Collins F., Treanor J., Rogers G., Citron M. β-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286(5440):735–741. doi: 10.1126/science.286.5440.735. PubMed DOI

Yan R., Bienkowski M.J., Shuck M.E., Miao H., Tory M.C., Pauley A.M., Brashier J.R., Stratman N.C., Mathews W.R., Buhl A.E., Carter D.B., Tomasselli A.G., Parodi L.A., Heinrikson R.L., Gurney M.E. Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Nature. 1999;402(6761):533–537. doi: 10.1038/990107. PubMed DOI

Lin X., Koelsch G., Wu S., Downs D., Dashti A., Tang J. Human aspartic protease memapsin 2 cleaves the β-secretase site of β-amyloid precursor protein. Proc. Natl. Acad. Sci. USA. 2000;97(4):1456–1460. doi: 10.1073/pnas.97.4.1456. PubMed DOI PMC

Barão S., Moechars D., Lichtenthaler S.F., De Strooper B. BACE1 Physiological functions may limit its use as therapeutic target for Alzheimer’s Disease. Trends Neurosci. 2016;39(3):158–169. doi: 10.1016/j.tins.2016.01.003. PubMed DOI

Motonaga K., Itoh M., Becker L.E., Goto Y., Takashima S. Elevated expression of beta-site amyloid precursor protein cleaving enzyme 2 in brains of patients with Down syndrome. Neurosci. Lett. 2002;326(1):64–66. doi: 10.1016/S0304-3940(02)00287-2. PubMed DOI

Head E., Powell D., Gold B.T., Schmitt F.A. Alzheimer’s Disease in Down Syndrome. Eur. J. Neurodegener. Dis. 2012;1(3):353–364. PubMed PMC

Head E., Lott I.T., Wilcock D.M., Lemere C.A. Aging in down syndrome and the development of Alzheimer’s Disease neuropathology. Curr. Alzheimer Res. 2016;13(1):18–29. doi: 10.2174/1567205012666151020114607. PubMed DOI PMC

Stockley J.H., O’Neill C. The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer’s disease brain. Biochem. Soc. Trans. 2007;35(Pt 3):574–576. doi: 10.1042/BST0350574. PubMed DOI

Murphy M.P., LeVine H., III Alzheimer’s disease and the amyloid-β peptide. J. Alzheimers Dis. 2010;19(1):311–323. doi: 10.3233/JAD-2010-1221. PubMed DOI PMC

Christensen M.A., Zhou W., Qing H., Lehman A., Philipsen S., Song W. Transcriptional regulation of BACE1, the β-amyloid precursor protein β-secretase, by Sp1. Mol. Cell. Biol. 2004;24(2):865–874. doi: 10.1128/MCB.24.2.865-874.2004. PubMed DOI PMC

Cole S.L., Vassar R. The basic biology of BACE1: A key therapeutic target for Alzheimer’s disease. Curr. Genomics. 2007;8(8):509–530. doi: 10.2174/138920207783769512. PubMed DOI PMC

Venugopal C., Demos C.M., Rao K.S.J., Pappolla M.A., Sambamurti K. Beta-secretase: structure, function, and evolution. CNS Neurol. Disord. Drug Targets. 2008;7(3):278–294. doi: 10.2174/187152708784936626. PubMed DOI PMC

Chow V.W., Mattson M.P., Wong P.C., Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med. 2010;12(1):1–12. doi: 10.1007/s12017-009-8104-z. PubMed DOI PMC

Lahiri D.K. Advances in Alzheimer’s Research. Sharjah: Bentham Science Publishers; 2013.

Wang R., Li J.J., Diao S., Kwak Y-D., Liu L., Zhi L., Büeler H., Bhat N.R., Williams R.W., Park E.A., Liao F-F. Metabolic stress modulates Alzheimer’s β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons. Cell Metab. 2013;17(5):685–694. doi: 10.1016/j.cmet.2013.03.016. PubMed DOI PMC

Chen C-H., Zhou W., Liu S., Deng Y., Cai F., Tone M., Tone Y., Tong Y., Song W. Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int. J. Neuropsychopharmacol. 2012;15(1):77–90. doi: 10.1017/S1461145711000149. PubMed DOI

Zhou W., Qing H., Tong Y., Song W. BACE1 gene expression and protein degradation. Ann. N. Y. Acad. Sci. 2004;1035:49–67. doi: 10.1196/annals.1332.004. PubMed DOI

Nowak K., Lange-Dohna C., Zeitschel U., Günther A., Lüscher B., Robitzki A., Perez-Polo R., Rossner S. The transcription factor Yin Yang 1 is an activator of BACE1 expression. J. Neurochem. 2006;96(6):1696–1707. doi: 10.1111/j.1471-4159.2006.03692.x. PubMed DOI

Hong H.S., Hwang E.M., Sim H.J., Cho H-J., Boo J.H., Oh S.S., Kim S.U., Mook-Jung I. Interferon γ stimulates β-secretase expression and sAPPbeta production in astrocytes. Biochem. Biophys. Res. Commun. 2003;307(4):922–927. doi: 10.1016/S0006-291X(03)01270-1. PubMed DOI

Menting K.W., Claassen J.A.H.R. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front. Aging Neurosci. 2014;6:165. doi: 10.3389/fnagi.2014.00165. PubMed DOI PMC

Zhou W., Cai F., Li Y., Yang G.S., O’Connor K.D., Holt R.A., Song W. BACE1 gene promoter single-nucleotide polymorphisms in Alzheimer’s disease. J. Mol. Neurosci. 2010;42(1):127–133. doi: 10.1007/s12031-010-9381-6. PubMed DOI

Cordner Z.A., Tamashiro K.L.K. Effects of chronic variable stress on cognition and Bace1 expression among wild-type mice. Transl. Psychiatry. 2016;6(7):e854. doi: 10.1038/tp.2016.127. PubMed DOI PMC

Zeng H., Huang P., Wang X., Wu J., Wu M., Huang J. Galangin-induced down-regulation of BACE1 by epigenetic mechanisms in SH-SY5Y cells. Neuroscience. 2015;294:172–181. doi: 10.1016/j.neuroscience.2015.02.054. PubMed DOI

Zhang N., Li W-W., Lv C-M., Gao Y-W., Liu X-L., Zhao L. miR-16-5p and miR-19b-3p prevent amyloid β-induced injury by targeting BACE1 in SH-SY5Y cells. Neuroreport. 2020;31(3):205–212. doi: 10.1097/WNR.0000000000001379. PubMed DOI

Barros-Viegas A.T., Carmona V., Ferreiro E., Guedes J., Cardoso A.M., Cunha P., Pereira de Almeida L., Resende de Oliveira C., Pedro de Magalhães J., Peça J., Cardoso A.L. miRNA-31 Improves cognition and abolishes Amyloid-β pathology by targeting app and bace1 in an animal model of Alzheimer’s disease. Mol. Ther. Nucleic Acids. 2020;19:1219–1236. doi: 10.1016/j.omtn.2020.01.010. PubMed DOI PMC

Miya Shaik M., Tamargo I.A., Abubakar M.B., Kamal M.A., Greig N.H., Gan S.H. The Role of microRNAs in Alzheimer’s disease and their therapeutic potentials. Genes (Basel) 2018;9(4):174. doi: 10.3390/genes9040174. PubMed DOI PMC

Deng Y., Ding Y., Hou D. Research status of the regulation of miRNA on BACE1. Int. J. Neurosci. 2014;124(7):474–477. doi: 10.3109/00207454.2013.858249. PubMed DOI

Kandalepas P.C., Vassar R. The normal and pathologic roles of the Alzheimer’s β-secretase, BACE1. Curr. Alzheimer Res. 2014;11(5):441–449. doi: 10.2174/1567205011666140604122059. PubMed DOI PMC

Vassar R. BACE1: the β-secretase enzyme in Alzheimer’s disease. J. Mol. Neurosci. 2004;23(1-2):105–114. doi: 10.1385/JMN:23:1-2:105. PubMed DOI

Vassar R. The β-secretase, BACE: a prime drug target for Alzheimer’s disease. J. Mol. Neurosci. 2001;17(2):157–170. doi: 10.1385/JMN:17:2:157. PubMed DOI

Yan R., Han P., Miao H., Greengard P., Xu H. The transmembrane domain of the Alzheimer’s β-secretase (BACE1) determines its late Golgi localization and access to β -amyloid precursor protein (APP) substrate. J. Biol. Chem. 2001;276(39):36788–36796. doi: 10.1074/jbc.M104350200. PubMed DOI

Holsinger R.M.D., Goense N., Bohorquez J., Strappe P. Splice variants of the Alzheimer’s disease beta-secretase, BACE1. Neurogenetics. 2013;14(1):1–9. doi: 10.1007/s10048-012-0348-3. PubMed DOI

Tanahashi H., Tabira T. Three novel alternatively spliced isoforms of the human beta-site amyloid precursor protein cleaving enzyme (BACE) and their effect on amyloid beta-peptide production. Neurosci. Lett. 2001;307(1):9–12. doi: 10.1016/S0304-3940(01)01912-7. PubMed DOI

Tan J., Evin G. B-site APP-cleaving enzyme 1 trafficking and Alzheimer’s disease pathogenesis. J. Neurochem. 2012;120(6):869–880. doi: 10.1111/j.1471-4159.2011.07623.x. PubMed DOI

Araki W. Post-translational regulation of the β-secretase BACE1. Brain Res. Bull. 2016;126(Pt 2):170–177. doi: 10.1016/j.brainresbull.2016.04.009. PubMed DOI

Vassar R., Kovacs D.M., Yan R., Wong P.C. The β-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J. Neurosci. 2009;29(41):12787–12794. doi: 10.1523/JNEUROSCI.3657-09.2009. PubMed DOI PMC

Haniu M., Denis P., Young Y., Mendiaz E.A., Fuller J., Hui J.O., Bennett B.D., Kahn S., Ross S., Burgess T., Katta V., Rogers G., Vassar R., Citron M. Characterization of Alzheimer’s β -secretase protein BACE. A pepsin family member with unusual properties. J. Biol. Chem. 2000;275(28):21099–21106. doi: 10.1074/jbc.M002095200. PubMed DOI

Vassar R., Kandalepas P.C. The β-secretase enzyme BACE1 as a therapeutic target for Alzheimer’s disease. Alzheimers Res. Ther. 2011;3(3):20. doi: 10.1186/alzrt82. PubMed DOI PMC

Costantini C., Ko M.H., Jonas M.C., Puglielli L. A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1. Biochem. J. 2007;407(3):383–395. doi: 10.1042/BJ20070040. PubMed DOI PMC

Walter J., Fluhrer R., Hartung B., Willem M., Kaether C., Capell A., Lammich S., Multhaup G., Haass C. Phosphorylation regulates intracellular trafficking of β-secretase. J. Biol. Chem. 2001;276(18):14634–14641. doi: 10.1074/jbc.M011116200. PubMed DOI

Yang H-C., Chai X., Mosior M., Kohn W., Boggs L.N., Erickson J.A., McClure D.B., Yeh W-K., Zhang L., Gonzalez-DeWhitt P., Mayer J.P., Martin J.A., Hu J., Chen S.H., Bueno A.B., Little S.P., McCarthy J.R., May P.C. Biochemical and kinetic characterization of BACE1: investigation into the putative species-specificity for β- and β′-cleavage sites by human and murine BACE1. J. Neurochem. 2004;91(6):1249–1259. doi: 10.1111/j.1471-4159.2004.02764.x. PubMed DOI

Motoki K., Kume H., Oda A., Tamaoka A., Hosaka A., Kametani F., Araki W. Neuronal β-amyloid generation is independent of lipid raft association of β-secretase BACE1: analysis with a palmitoylation-deficient mutant. Brain Behav. 2012;2(3):270–282. doi: 10.1002/brb3.52. PubMed DOI PMC

Vetrivel K.S., Meckler X., Chen Y., Nguyen P.D., Seidah N.G., Vassar R., Wong P.C., Fukata M., Kounnas M.Z., Thinakaran G. Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts. J. Biol. Chem. 2009;284(6):3793–3803. doi: 10.1074/jbc.M808920200. PubMed DOI PMC

Kalvodova L., Kahya N., Schwille P., Ehehalt R., Verkade P., Drechsel D., Simons K. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J. Biol. Chem. 2005;280(44):36815–36823. doi: 10.1074/jbc.M504484200. PubMed DOI

Cordy J.M., Hooper N.M., Turner A.J., Turner A.J. The involvement of lipid rafts in Alzheimer’s disease. Mol. Membr. Biol. 2006;23(1):111–122. doi: 10.1080/09687860500496417. PubMed DOI

Cordy J.M., Hussain I., Dingwall C., Hooper N.M., Turner A.J. Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. USA. 2003;100(20):11735–11740. doi: 10.1073/pnas.1635130100. PubMed DOI PMC

Hirst J., Lui W.W.Y., Bright N.A., Totty N., Seaman M.N.J., Robinson M.S. A family of proteins with γ-adaptin and VHS domains that facilitate trafficking between the trans-Golgi network and the vacuole/lysosome. J. Cell Biol. 2000;149(1):67–80. doi: 10.1083/jcb.149.1.67. PubMed DOI PMC

He X., Li F., Chang W-P., Tang J. GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J. Biol. Chem. 2005;280(12):11696–11703. doi: 10.1074/jbc.M411296200. PubMed DOI

Ghosh P., Kornfeld S. The GGA proteins: key players in protein sorting at the trans-Golgi network. Eur. J. Cell Biol. 2004;83(6):257–262. doi: 10.1078/0171-9335-00374. PubMed DOI

von Einem B., Wahler A., Schips T., Serrano-Pozo A., Proepper C., Boeckers T.M., Rueck A., Wirth T., Hyman B.T., Danzer K.M., Thal D.R., von Arnim C.A.F. The Golgi-Localized γ-ear-containing arf-binding (gga) proteins alter Amyloid-β precursor protein (app) processing through interaction of their gae domain with the beta-site app cleaving enzyme 1 (BACE1). PLoS One. 2015;10(6):e0129047. doi: 10.1371/journal.pone.0129047. PubMed DOI PMC

Tesco G., Koh Y.H., Kang E.L., Cameron A.N., Das S., Sena-Esteves M., Hiltunen M., Yang S-H., Zhong Z., Shen Y., Simpkins J.W., Tanzi R.E. Depletion of GGA3 stabilizes BACE and enhances β-secretase activity. Neuron. 2007;54(5):721–737. doi: 10.1016/j.neuron.2007.05.012. PubMed DOI PMC

Deng M., He W., Tan Y., Han H., Hu X., Xia K., Zhang Z., Yan R. Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme 1. J. Biol. Chem. 2013;288(42):30236–30245. doi: 10.1074/jbc.M113.480079. PubMed DOI PMC

Murayama K.S., Kametani F., Saito S., Kume H., Akiyama H., Araki W. Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid β-protein. Eur. J. Neurosci. 2006;24(5):1237–1244. doi: 10.1111/j.1460-9568.2006.05005.x. PubMed DOI

Zhao Y., Wang Y., Yang J., Wang X., Zhao Y., Zhang X., Zhang Y.W. Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. Mol. Neurodegener. 2012;7:30. doi: 10.1186/1750-1326-7-30. PubMed DOI PMC

Okada H., Zhang W., Peterhoff C., Hwang J.C., Nixon R.A., Ryu S.H., Kim T-W. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010;24(8):2783–2794. doi: 10.1096/fj.09-146357. PubMed DOI PMC

Kandalepas P.C., Vassar R. Identification and biology of β-secretase. J. Neurochem. 2012;120(Suppl. 1):55–61. doi: 10.1111/j.1471-4159.2011.07512.x. PubMed DOI

Dislich B., Wohlrab F., Bachhuber T., Müller S.A., Kuhn P-H., Hogl S., Meyer-Luehmann M., Lichtenthaler S.F. Label-free Quantitative proteomics of mouse cerebrospinal fluid detects β-site app cleaving enzyme (bace1) protease substrates In Vivo. Mol. Cell. Proteomics. 2015;14(10):2550–2563. doi: 10.1074/mcp.M114.041533. PubMed DOI PMC

Hemming M.L., Elias J.E., Gygi S.P., Selkoe D.J. Identification of β-secretase (BACE1) substrates using quantitative proteomics. PLoS One. 2009;4(12):e8477. doi: 10.1371/journal.pone.0008477. PubMed DOI PMC

Munro K.M., Nash A., Pigoni M., Lichtenthaler S.F., Gunnersen J.M. Functions of the Alzheimer’s disease protease bace1 at the synapse in the central nervous system. J. Mol. Neurosci. 2016;60(3):305–315. doi: 10.1007/s12031-016-0800-1. PubMed DOI PMC

Yan R. Physiological functions of the β-Site amyloid precursor protein cleaving enzyme 1 and 2. Front. Mol. Neurosci. 2017;10:97. doi: 10.3389/fnmol.2017.00097. PubMed DOI PMC

Hu X., Hicks C.W., He W., Wong P., Macklin W.B., Trapp B.D., Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 2006;9(12):1520–1525. doi: 10.1038/nn1797. PubMed DOI

Fleck D., Garratt A.N., Haass C., Willem M. BACE1 dependent neuregulin processing. Curr. Alzheimer Res. 2012;9(2):178–183. doi: 10.2174/156720512799361637. [review]. PubMed DOI

Wansbury O., Panchal H., James M., Parry S., Ashworth A., Howard B. Dynamic expression of Erbb pathway members during early mammary gland morphogenesis. J. Invest. Dermatol. 2008;128(4):1009–1021. doi: 10.1038/sj.jid.5701118. PubMed DOI

Zhou L., Barão S., Laga M., Bockstael K., Borgers M., Gijsen H., Annaert W., Moechars D., Mercken M., Gevaert K., De Strooper B. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J. Biol. Chem. 2012;287(31):25927–25940. doi: 10.1074/jbc.M112.377465. PubMed DOI PMC

Vassar R. Editorial: Implications for BACE1 inhibitor clinical trials: adult conditional bace1 knockout mice exhibit axonal Organization defects in the Hippocampus. J. Prev. Alzheimers Dis. 2019;6(2):78–84. PubMed

Ou-Yang M-H., Kurz J.E., Nomura T., Popovic J., Rajapaksha T.W., Dong H., Contractor A., Chetkovich D.M., Tourtellotte W.G., Vassar R. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci. Transl. Med. 2018;10(459):eaao5620. doi: 10.1126/scitranslmed.aao5620. PubMed DOI PMC

Mayer M.C., Schauenburg L., Thompson-Steckel G., Dunsing V., Kaden D., Voigt P., Schaefer M., Chiantia S., Kennedy T.E., Multhaup G. Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2. J. Neurochem. 2016;137(2):266–276. doi: 10.1111/jnc.13540. PubMed DOI

Heber S., Herms J., Gajic V., Hainfellner J., Aguzzi A., Rülicke T., von Kretzschmar H., von Koch C., Sisodia S., Tremml P., Lipp H-P., Wolfer D.P., Müller U. Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J. Neurosci. 2000;20(21):7951–7963. doi: 10.1523/JNEUROSCI.20-21-07951.2000. PubMed DOI PMC

Han K., Müller U.C., Hülsmann S. Amyloid-precursor like proteins aplp1 and aplp2 are dispensable for normal development of the neonatal respiratory network. Front. Mol. Neurosci. 2017;10:189. doi: 10.3389/fnmol.2017.00189. PubMed DOI PMC

Kim D.Y., Carey B.W., Wang H., Ingano L.A.M., Binshtok A.M., Wertz M.H., Pettingell W.H., He P., Lee V.M-Y., Woolf C.J., Kovacs D.M. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat. Cell Biol. 2007;9(7):755–764. doi: 10.1038/ncb1602. PubMed DOI PMC

Bouza A.A., Isom L.L. Voltage-gated sodium channel β subunits and their related diseases. Handb. Exp. Pharmacol. 2018;246:423–450. doi: 10.1007/164_2017_48. PubMed DOI PMC

Kitazume S., Tachida Y., Oka R., Kotani N., Ogawa K., Suzuki M., Dohmae N., Takio K., Saido T.C., Hashimoto Y. Characterization of alpha 2,6-sialyltransferase cleavage by Alzheimer’s β -secretase (BACE1). J. Biol. Chem. 2003;278(17):14865–14871. doi: 10.1074/jbc.M206262200. PubMed DOI

Kitazume S., Suzuki M., Saido T.C., Hashimoto Y. Involvement of proteases in glycosyltransferase secretion: Alzheimer’s beta-secretase-dependent cleavage and a following processing by an aminopeptidase. Glycoconj. J. 2004;21(1-2):25–29. doi: 10.1023/B:GLYC.0000043743.21735.ff. PubMed DOI

Kitazume S., Oka R., Ogawa K., Futakawa S., Hagiwara Y., Takikawa H., Kato M., Kasahara A., Miyoshi E., Taniguchi N., Hashimoto Y. Molecular insights into β-galactoside alpha2,6-sialyltransferase secretion in vivo. Glycobiology. 2009;19(5):479–487. doi: 10.1093/glycob/cwp003. PubMed DOI

Deng X., Zhang J., Liu Y., Chen L., Yu C. TNF-α regulates the proteolytic degradation of ST6Gal-1 and endothelial cell-cell junctions through upregulating expression of BACE1. Sci. Rep. 2017;7:40256. doi: 10.1038/srep40256. PubMed DOI PMC

Sugimoto I., Futakawa S., Oka R., Ogawa K., Marth J.D., Miyoshi E., Taniguchi N., Hashimoto Y., Kitazume S. β-galactoside alpha2,6-sialyltransferase I cleavage by BACE1 enhances the sialylation of soluble glycoproteins. A novel regulatory mechanism for alpha2,6-sialylation. J. Biol. Chem. 2007;282(48):34896–34903. doi: 10.1074/jbc.M704766200. PubMed DOI

von Arnim C.A.F., Kinoshita A., Peltan I.D., Tangredi M.M., Herl L., Lee B.M., Spoelgen R., Hshieh T.T., Ranganathan S., Battey F.D., Liu C-X., Bacskai B.J., Sever S., Irizarry M.C., Strickland D.K., Hyman B.T. The low density lipoprotein receptor-related protein (LRP) is a novel β-secretase (BACE1) substrate. J. Biol. Chem. 2005;280(18):17777–17785. doi: 10.1074/jbc.M414248200. PubMed DOI

Jaeger S., Pietrzik C.U. Functional role of lipoprotein receptors in Alzheimer’s disease. Curr. Alzheimer Res. 2008;5(1):15–25. doi: 10.2174/156720508783884675. PubMed DOI

Ulery P.G., Strickland D.K. LRP in Alzheimer’s disease: friend or foe? J. Clin. Invest. 2000;106(9):1077–1079. doi: 10.1172/JCI11455. PubMed DOI PMC

Tanokashira D., Motoki K., Minegishi S., Hosaka A., Mamada N., Tamaoka A., Okada T., Lakshmana M.K., Araki W. LRP1 Downregulates the Alzheimer’s β-Secretase BACE1 by modulating its intraneuronal trafficking. 2015. PubMed PMC

Shinohara M., Tachibana M., Kanekiyo T., Bu G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J. Lipid Res. 2017;58(7):1267–1281. doi: 10.1194/jlr.R075796. PubMed DOI PMC

Ohno M. PERK as a hub of multiple pathogenic pathways leading to memory deficits and neurodegeneration in Alzheimer’s disease. Brain Res. Bull. 2018;141:72–78. doi: 10.1016/j.brainresbull.2017.08.007. PubMed DOI

Hashimoto S., Saido T.C. Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer’s disease. Open Biol. 2018;8(4):180024. doi: 10.1098/rsob.180024. PubMed DOI PMC

Southan C., Hancock J.M. A tale of two drug targets: the evolutionary history of BACE1 and BACE2. Front. Genet. 2013;4:293. doi: 10.3389/fgene.2013.00293. PubMed DOI PMC

Mullard A. BACE inhibitor bust in Alzheimer trial. Nat. Rev. Drug Discov. 2017;16(3):155. PubMed

Yan R., Vassar R. Targeting the β secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol. 2014;13(3):319–329. doi: 10.1016/S1474-4422(13)70276-X. PubMed DOI PMC

Fluhrer R., Capell A., Westmeyer G., Willem M., Hartung B., Condron M.M., Teplow D.B., Haass C., Walter J. A non-amyloidogenic function of BACE-2 in the secretory pathway. J. Neurochem. 2002;81(5):1011–1020. doi: 10.1046/j.1471-4159.2002.00908.x. PubMed DOI

Yan R., Munzner J.B., Shuck M.E., Bienkowski M.J. BACE2 functions as an alternative α-secretase in cells. J. Biol. Chem. 2001;276(36):34019–34027. doi: 10.1074/jbc.M105583200. PubMed DOI

Sun X., He G., Song W. BACE2, as a novel APP θ-secretase, is not responsible for the pathogenesis of Alzheimer’s disease in Down syndrome. FASEB J. 2006;20(9):1369–1376. doi: 10.1096/fj.05-5632com. PubMed DOI

Wang Z., Xu Q., Cai F., Liu X., Wu Y., Song W. BACE2, a conditional β-secretase, contributes to Alzheimer’s disease pathogenesis. JCI Insight. 2019;4(1):e123431. doi: 10.1172/jci.insight.123431. PubMed DOI PMC

Fukumoto H., Rosene D.L., Moss M.B., Raju S., Hyman B.T., Irizarry M.C. β-secretase activity increases with aging in human, monkey, and mouse brain. Am. J. Pathol. 2004;164(2):719–725. doi: 10.1016/S0002-9440(10)63159-8. PubMed DOI PMC

Voytyuk I., Mueller S.A., Herber J., Snellinx A., Moechars D., van Loo G., Lichtenthaler S.F., De Strooper B. BACE2 distribution in major brain cell types and identification of novel substrates. Life Sci Alliance. 2018;1(1):e201800026. doi: 10.26508/lsa.201800026. PubMed DOI PMC

Esterházy D., Stützer I., Wang H., Rechsteiner M.P., Beauchamp J., Döbeli H., Hilpert H., Matile H., Prummer M., Schmidt A., Lieske N., Boehm B., Marselli L., Bosco D., Kerr-Conte J., Aebersold R., Spinas G.A., Moch H., Migliorini C., Stoffel M. Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell Metab. 2011;14(3):365–377. doi: 10.1016/j.cmet.2011.06.018. PubMed DOI

Stützer I., Selevsek N., Esterházy D., Schmidt A., Aebersold R., Stoffel M. Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cells. J. Biol. Chem. 2013;288(15):10536–10547. doi: 10.1074/jbc.M112.444703. PubMed DOI PMC

Shimshek D.R., Jacobson L.H., Kolly C., Zamurovic N., Balavenkatraman K.K., Morawiec L., Kreutzer R., Schelle J., Jucker M., Bertschi B., Theil D., Heier A., Bigot K., Beltz K., Machauer R., Brzak I., Perrot L., Neumann U. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Sci. Rep. 2016;6:21917. doi: 10.1038/srep21917. PubMed DOI PMC

Jamieson C., Moir E.M., Rankovic Z., Wishart G. Medicinal chemistry of hERG optimizations: Highlights and hang-ups. J. Med. Chem. 2006;49(17):5029–5046. doi: 10.1021/jm060379l. PubMed DOI

Ginman T., Viklund J., Malmström J., Blid J., Emond R., Forsblom R., Johansson A., Kers A., Lake F., Sehgelmeble F., Sterky K.J., Bergh M., Lindgren A., Johansson P., Jeppsson F., Fälting J., Gravenfors Y., Rahm F. Core refinement toward permeable β-secretase (BACE-1) inhibitors with low hERG activity. J. Med. Chem. 2013;56(11):4181–4205. doi: 10.1021/jm3011349. PubMed DOI

Dineen T.A., Chen K., Cheng A.C., Derakhchan K., Epstein O., Esmay J., Hickman D., Kreiman C.E., Marx I.E., Wahl R.C., Wen P.H., Weiss M.M., Whittington D.A., Wood S., Fremeau R.T., Jr, White R.D., Patel V.F. Inhibitors of β-site amyloid precursor protein cleaving enzyme (BACE1): identification of (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5‘H-spiro[chromeno[2,3-b]pyridine-5,4’-oxazol]-2′-amine (AMG-8718). J. Med. Chem. 2014;57(23):9811–9831. doi: 10.1021/jm5012676. PubMed DOI

Rampe D., Brown A.M. A history of the role of the hERG channel in cardiac risk assessment. J. Pharmacol. Toxicol. Methods. 2013;68(1):13–22. doi: 10.1016/j.vascn.2013.03.005. PubMed DOI

Greco S., Zaccagnini G., Fuschi P., Voellenkle C., Carrara M., Sadeghi I., Bearzi C., Maimone B., Castelvecchio S., Stellos K., Gaetano C., Menicanti L., Martelli F. Increased BACE1-AS long noncoding RNA and β-amyloid levels in heart failure. Cardiovasc. Res. 2017;113(5):453–463. doi: 10.1093/cvr/cvx013. PubMed DOI

Troncone L., Luciani M., Coggins M., Wilker E.H., Ho C-Y., Codispoti K.E., Frosch M.P., Kayed R., Del Monte F. Aβ Amyloid pathology affects the hearts of patients with alzheimer’s disease: mind the heart. J. Am. Coll. Cardiol. 2016;68(22):2395–2407. doi: 10.1016/j.jacc.2016.08.073. PubMed DOI PMC

Zuhl A.M., Nolan C.E., Brodney M.A., Niessen S., Atchison K., Houle C., Karanian D.A., Ambroise C., Brulet J.W., Beck E.M., Doran S.D., O’Neill B.T., Am Ende C.W., Chang C., Geoghegan K.F., West G.M., Judkins J.C., Hou X., Riddell D.R., Johnson D.S. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors. Nat. Commun. 2016;7:13042. doi: 10.1038/ncomms13042. PubMed DOI PMC

Koike M., Nakanishi H., Saftig P., Ezaki J., Isahara K., Ohsawa Y., Schulz-Schaeffer W., Watanabe T., Waguri S., Kametaka S., Shibata M., Yamamoto K., Kominami E., Peters C., von Figura K., Uchiyama Y. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. J. Neurosci. 2000;20(18):6898–6906. doi: 10.1523/JNEUROSCI.20-18-06898.2000. PubMed DOI PMC

Steinfeld R., Reinhardt K., Schreiber K., Hillebrand M., Kraetzner R., Brück W., Saftig P., Gärtner J., Cathepsin D. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am. J. Hum. Genet. 2006;78(6):988–998. doi: 10.1086/504159. PubMed DOI PMC

Tsukuba T., Okamoto K., Okamoto Y., Yanagawa M., Kohmura K., Yasuda Y., Uchi H., Nakahara T., Furue M., Nakayama K., Kadowaki T., Yamamoto K., Nakayama K.I. Association of cathepsin E deficiency with development of atopic dermatitis. J. Biochem. 2003;134(6):893–902. doi: 10.1093/jb/mvg216. PubMed DOI

www.alzforum.org/news/conference-coverage/picking-through-rubble-field-tries-salvage-bace-inhibitors

U. S. National Library of Medicine https://clinicaltrials.gov/ ct2/show/NCT01537757 PubMed

Hansen R.A., Gartlehner G., Webb A.P., Morgan L.C., Moore C.G., Jonas D.E. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin. Interv. Aging. 2008;3(2):211–225. PubMed PMC

Colović M.B., Krstić D.Z., Lazarević-Pašti T.D., Bondžić A.M., Vasić V.M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr. Neuropharmacol. 2013;11(3):315–335. doi: 10.2174/1570159X11311030006. PubMed DOI PMC

Canter R.G., Penney J., Tsai L-H. The road to restoring neural circuits for the treatment of Alzheimer’s disease. Nature. 2016;539(7628):187–196. doi: 10.1038/nature20412. PubMed DOI

de Miranda L.F.J.R., Barbosa M.D.A., Peles P.R.H., Pôças P.H., Tito P.A.L., Matoso R.O., de Lima T.O.L., de Moraes E.N., Caramelli P. Good rate of clinical response to cholinesterase inhibitors in mild and moderate Alzheimer’s disease after three months of treatment: An open-label study. Dement. Neuropsychol. 2013;7(2):190–196. doi: 10.1590/S1980-57642013DN70200009. PubMed DOI PMC

Bray S.J. Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 2006;7(9):678–689. doi: 10.1038/nrm2009. PubMed DOI

Bray S.J. Notch signalling in context. Nat. Rev. Mol. Cell Biol. 2016;17(11):722–735. doi: 10.1038/nrm.2016.94. PubMed DOI

De Strooper B., Vassar R., Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 2010;6(2):99–107. doi: 10.1038/nrneurol.2009.218. PubMed DOI PMC

Basi G., Frigon N., Barbour R., Doan T., Gordon G., McConlogue L., Sinha S., Zeller M. Antagonistic effects of β-site amyloid precursor protein-cleaving enzymes 1 and 2 on β-amyloid peptide production in cells. J. Biol. Chem. 2003;278(34):31512–31520. doi: 10.1074/jbc.M300169200. PubMed DOI

Vassar R., Kuhn P-H., Haass C., Kennedy M.E., Rajendran L., Wong P.C., Lichtenthaler S.F. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J. Neurochem. 2014;130(1):4–28. doi: 10.1111/jnc.12715. PubMed DOI PMC

Coimbra J.R.M., Marques D.F.F., Baptista S.J., Pereira C.M.F., Moreira P.I., Dinis T.C.P., Santos A.E., Salvador J.A.R. Highlights in BACE1 Inhibitors for Alzheimer’s Disease Treatment. Front Chem. 2018;6:178. doi: 10.3389/fchem.2018.00178. PubMed DOI PMC

Chang W-P., Koelsch G., Wong S., Downs D., Da H., Weerasena V., Gordon B., Devasamudram T., Bilcer G., Ghosh A.K., Tang J. In vivo inhibition of Abeta production by memapsin 2 (β-secretase) inhibitors. J. Neurochem. 2004;89(6):1409–1416. doi: 10.1111/j.1471-4159.2004.02452.x. PubMed DOI

Luo X., Yan R. Inhibition of BACE1 for therapeutic use in Alzheimer’s disease. Int. J. Clin. Exp. Pathol. 2010;3(6):618–628. PubMed PMC

Yuan J., Venkatraman S., Zheng Y., McKeever B.M., Dillard L.W., Singh S.B. Structure-based design of β-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease. J. Med. Chem. 2013;56(11):4156–4180. doi: 10.1021/jm301659n. PubMed DOI

Hong L., Koelsch G., Lin X., Wu S., Terzyan S., Ghosh A.K., Zhang X.C., Tang J. Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor. Science. 2000;290(5489):150–153. doi: 10.1126/science.290.5489.150. PubMed DOI

Shimizu H., Tosaki A., Kaneko K., Hisano T., Sakurai T., Nukina N. Crystal structure of an active form of BACE1, an enzyme responsible for amyloid β protein production. Mol. Cell. Biol. 2008;28(11):3663–3671. doi: 10.1128/MCB.02185-07. PubMed DOI PMC

Hu B., Xiong B., Qiu B.Y., Li X., Yu H.P., Xiao K., Wang X., Li J., Shen J.K. Construction of a small peptide library related to inhibitor OM99-2 and its structure-activity relationship to β-secretase. Acta Pharmacol. Sin. 2006;27(12):1586–1593. doi: 10.1111/j.1745-7254.2006.00432.x. PubMed DOI

Ghosh A.K., Shin D., Downs D., Koelsch G., Lin X., Ermolieff J., Tang J. Design of potent inhibitors for human brain memapsin 2 (β-Secretase). J. Am. Chem. Soc. 2000;122(14):3522–3523. doi: 10.1021/ja000300g. PubMed DOI PMC

Ben Halima S., Mishra S., Raja K.M.P., Willem M., Baici A., Simons K., Brüstle O., Koch P., Haass C., Caflisch A., Rajendran L. Specific inhibition of β-Secretase processing of the Alzheimer Disease amyloid precursor protein. Cell Rep. 2016;14(9):2127–2141. doi: 10.1016/j.celrep.2016.01.076. PubMed DOI

Hernández-Rodríguez M., Correa-Basurto J., Martínez-Ramos F., Padilla-Martínez I.I., Benítez-Cardoza C.G., Mera-Jiménez E., Rosales-Hernández M.C. Design of multi-target compounds as AChE, BACE1, and amyloid-β(1-42) oligomerization inhibitors: in silico and in vitro studies. J. Alzheimers Dis. 2014;41(4):1073–1085. doi: 10.3233/JAD-140471. PubMed DOI

Qu F., Yang M., Rasooly A. Dual signal amplification electrochemical biosensor for monitoring the activity and inhibition of the Alzheimer’s Related Protease β-Secretase. Anal. Chem. 2016;88(21):10559–10565. doi: 10.1021/acs.analchem.6b02659. PubMed DOI

Ellis C.R., Tsai C-C., Lin F-Y., Shen J. Conformational dynamics of cathepsin D and binding to a small-molecule BACE1 inhibitor. J. Comput. Chem. 2017;38(15):1260–1269. doi: 10.1002/jcc.24719. PubMed DOI PMC

May P.C., Dean R.A., Lowe S.L., Martenyi F., Sheehan S.M., Boggs L.N., Monk S.A., Mathes B.M., Mergott D.J., Watson B.M., Stout S.L., Timm D.E., Smith Labell E., Gonzales C.R., Nakano M., Jhee S.S., Yen M., Ereshefsky L., Lindstrom T.D., Calligaro D.O., Cocke P.J., Greg Hall D., Friedrich S., Citron M., Audia J.E. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J. Neurosci. 2011;31(46):16507–16516. doi: 10.1523/JNEUROSCI.3647-11.2011. PubMed DOI PMC

Fielden M.R., Werner J., Jamison J.A., Coppi A., Hickman D., Dunn R.T., II, Trueblood E., Zhou L., Afshari C.A., Lightfoot-Dunn R. Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat. Toxicol. Pathol. 2015;43(4):581–592. doi: 10.1177/0192623314553804. PubMed DOI

Yan R. Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl. Neurodegener. 2016;5:13. doi: 10.1186/s40035-016-0061-5. PubMed DOI PMC

Maia M.A., Sousa E. BACE-1 and γ-Secretase as therapeutic targets for Alzheimer’s Disease. Pharmaceuticals (Basel) 2019;12(1):41. doi: 10.3390/ph12010041. PubMed DOI PMC

Egan M.F., Kost J., Voss T., Mukai Y., Aisen P.S., Cummings J.L., Tariot P.N., Vellas B., van Dyck C.H., Boada M., Zhang Y., Li W., Furtek C., Mahoney E., Harper M.L., Mo Y., Sur C., Michelson D. Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease. N. Engl. J. Med. 2019;380(15):1408–1420. doi: 10.1056/NEJMoa1812840. PubMed DOI PMC

Das B., Yan R. A Close Look at BACE1 Inhibitors for Alzheimer’s Disease treatment. CNS Drugs. 2019;33(3):251–263. doi: 10.1007/s40263-019-00613-7. PubMed DOI PMC

Wessels A.M., Tariot P.N., Zimmer J.A., Selzler K.J., Bragg S.M., Andersen S.W., Landry J., Krull J.H., Downing A.M., Willis B.A., Shcherbinin S., Mullen J., Barker P., Schumi J., Shering C., Matthews B.R., Stern R.A., Vellas B., Cohen S., MacSweeney E., Boada M., Sims J.R. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. JAMA Neurol. 2019;77:199–209. doi: 10.1001/jamaneurol.2019.3988. PubMed DOI PMC

Timmers M., Van Broeck B., Ramael S., Slemmon J., De Waepenaert K., Russu A., Bogert J., Stieltjes H., Shaw L.M., Engelborghs S., Moechars D., Mercken M., Liu E., Sinha V., Kemp J., Van Nueten L., Tritsmans L., Streffer J.R. Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor. Alzheimers Dement. (N. Y.) 2016;2(3):202–212. doi: 10.1016/j.trci.2016.08.001. PubMed DOI PMC

Henley D., Raghavan N., Sperling R., Aisen P., Raman R., Romano G. Preliminary results of a trial of atabecestat in preclinical Alzheimer’s Disease. N. Engl. J. Med. 2019;380(15):1483–1485. doi: 10.1056/NEJMc1813435. PubMed DOI

Lahiri D.K., Maloney B., Long J.M., Greig N.H. Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimers Dement. 2014;10(5) Suppl.:S411–S419. doi: 10.1016/j.jalz.2013.11.004. PubMed DOI PMC

Kennedy M.E., Wang W., Song L., Lee J., Zhang L., Wong G., Wang L., Parker E. Measuring human beta-secretase (BACE1) activity using homogeneous time-resolved fluorescence. Anal. Biochem. 2003;319(1):49–55. doi: 10.1016/S0003-2697(03)00253-7. PubMed DOI

Eketjäll S., Janson J., Kaspersson K., Bogstedt A., Jeppsson F., Fälting J., Haeberlein S.B., Kugler A.R., Alexander R.C., Cebers G. AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis. 2016;50(4):1109–1123. doi: 10.3233/JAD-150834. PubMed DOI PMC

InvivoChem www.invivochem.com/atabecestat-jnj-54861911.html

Neumann U., Ufer M., Jacobson L.H., Rouzade-Dominguez M.L., Huledal G., Kolly C., Lüönd R.M., Machauer R., Veenstra S.J., Hurth K., Rueeger H., Tintelnot-Blomley M., Staufenbiel M., Shimshek D.R., Perrot L., Frieauff W., Dubost V., Schiller H., Vogg B., Beltz K., Avrameas A., Kretz S., Pezous N., Rondeau J.M., Beckmann N., Hartmann A., Vormfelde S., David O.J., Galli B., Ramos R., Graf A., Lopez L.C. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med. 2018;10(11):e9316. doi: 10.15252/emmm.201809316. PubMed DOI PMC

Ufer M., Rouzade-Dominguez M-L., Huledal G., Pezous N., Avrameas A., David O., Kretz S., Kucher K., Neumann U., Cha J-H., Graf A., Lopez-Lopez C. Results from a first-in-human study with the bace inhibitor cnp520. Alzheimers Dement. J. Alzheimers Assoc. 2016;12:200. doi: 10.1016/j.jalz.2016.06.351. DOI

Dobrowolska Z.J.A., Vassar R.J.A. A promising, novel, and unique BACE1 inhibitor emerges in the quest to prevent Alzheimer’s disease. EMBO Mol. Med. 2018;10(11):e9717. doi: 10.15252/emmm.201809717. PubMed DOI PMC

www.alzforum.org/news/research-news/cognitive-decline-trips-api-trials-bace-inhibitor

Lynch S.Y., Kaplow J., Zhao J., Dhadda S., Luthman J., Albala B. elenbecestat, e2609, a bace inhibitor: results from a phase-2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to alzheimer’s disease. Alzheimers Dement. J. Alzheimers Assoc. 2018;14:1623. doi: 10.1016/j.jalz.2018.07.213. DOI

www.alzforum.org/therapeutics/elenbecestat

Panza F., Lozupone M., Solfrizzi V., Sardone R., Piccininni C., Dibello V., Stallone R., Giannelli G., Bellomo A., Greco A., Daniele A., Seripa D., Logroscino G., Imbimbo B.P. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev. Neurother. 2018;18(11):847–857. doi: 10.1080/14737175.2018.1531706. PubMed DOI

http://eisai.mediaroom.com/2019-09-13-

O’Neill B.T., Beck E.M., Butler C.R., Nolan C.E., Gonzales C., Zhang L., Doran S.D., Lapham K., Buzon L.M., Dutra J.K., Barreiro G., Hou X., Martinez-Alsina L.A., Rogers B.N., Villalobos A., Murray J.C., Ogilvie K., LaChapelle E.A., Chang C., Lanyon L.F., Steppan C.M., Robshaw A., Hales K., Boucher G.G., Pandher K., Houle C., Ambroise C.W., Karanian D., Riddell D., Bales K.R., Brodney M.A. Design and Synthesis of Clinical Candidate PF-06751979: A potent, brain penetrant, β-site amyloid precursor protein cleaving enzyme 1 (bace1) inhibitor lacking hypopigmentation. J. Med. Chem. 2018;61(10):4476–4504. doi: 10.1021/acs.jmedchem.8b00246. PubMed DOI

McKinzie D.L., May P.C., Boggs L.N., Yang Z., Brier R.A., Monk S.A., Willis B.A., Borders A.R., Winneroski L.L., Green S.J., Mergott D.J. Nonclinical pharmacological characterization of the bace1 inhibitor ly3202626. Alzheimers Dement. 2016;12:432–P433. doi: 10.1016/j.jalz.2016.06.828. DOI

Willis B.A., Lowe S.L., Daugherty L.L., Dean R.A., English B., Ereshefsky L., Gevorkyan H., James D.E., Jhee S., Lin Q., Lo A., Mergott D.J., Monk S.A., Nakano M., Zimmer J.A., Irizarry M.C. Pharmacokinetics, pharmacodynamics, safety, and tolerability of ly3202626, a novel bace1 inhibitor, in healthy subjects and patients with Alzheimer’s Disease. Alzheimers Dement. 2016;12:418–P418. doi: 10.1016/j.jalz.2016.06.791. DOI

Gardner J. www.evaluate.com/vantage/articles/ analysis/spotlight/eli-lilly-backs-away-bace-not-novel-alzheimers-targets

McElrath K.J. Why has pfizer discontinued research on neurodegenerative diseases? https://drugsafetynews.com/2018/03/13/ why-has-pfizer-discontinued-research-on-neurodegenerative-diseases/

Ali M.Y., Jannat S., Edraki N., Das S., Chang W.K., Kim H.C., Park S.K., Chang M.S. Flavanone glycosides inhibit β-site amyloid precursor protein cleaving enzyme 1 and cholinesterase and reduce Aβ aggregation in the amyloidogenic pathway. Chem. Biol. Interact. 2019;309:108707. doi: 10.1016/j.cbi.2019.06.020. PubMed DOI

Mezeiova E., Spilovska K., Nepovimova E., Gorecki L., Soukup O., Dolezal R., Malinak D., Janockova J., Jun D., Kuca K., Korabecny J. Profiling donepezil template into multipotent hybrids with antioxidant properties. J. Enzyme Inhib. Med. Chem. 2018;33(1):583–606. doi: 10.1080/14756366.2018.1443326. PubMed DOI PMC

Ghobadian R., Mahdavi M., Nadri H., Moradi A., Edraki N., Akbarzadeh T., Sharifzadeh M., Bukhari S.N.A., Amini M. Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities. Eur. J. Med. Chem. 2018;155:49–60. doi: 10.1016/j.ejmech.2018.05.031. PubMed DOI

Neumann U., Machauer R., Shimshek D.R. The β-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-β reduction to downstream disease-relevant effects. Br. J. Pharmacol. 2019;176(18):3435–3446. doi: 10.1111/bph.14582. PubMed DOI PMC

Winneroski L.L., Erickson J.A., Green S.J., Lopez J.E., Stout S.L., Porter W.J., Timm D.E., Audia J.E., Barberis M., Beck J.P., Boggs L.N., Borders A.R., Boyer R.D., Brier R.A., Hembre E.J., Hendle J., Garcia-Losada P., Minguez J.M., Mathes B.M., May P.C., Monk S.A., Rankovic Z., Shi Y., Watson B.M., Yang Z., Mergott D.J. Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints. Bioorg. Med. Chem. 2020;28(1):115194. doi: 10.1016/j.bmc.2019.115194. PubMed DOI

Nakamura A., Kaneko N., Villemagne V.L., Kato T., Doecke J., Doré V., Fowler C., Li Q-X., Martins R., Rowe C., Tomita T., Matsuzaki K., Ishii K., Ishii K., Arahata Y., Iwamoto S., Ito K., Tanaka K., Masters C.L., Yanagisawa K. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018;554(7691):249–254. doi: 10.1038/nature25456. PubMed DOI

Albala B., Kaplow J.M., Lai R., Matijevic M., Aluri J., Satlin A. CSF amyloid lowering in human volunteers after 14 days’ oral administration of the novel bace1 inhibitor e2609. Alzheimers Dement. J. Alzheimers Assoc. 2012;8:S743. doi: 10.1016/j.jalz.2013.08.023. DOI

Kennedy M.E., Stamford A.W., Chen X., Cox K., Cumming J.N., Dockendorf M.F., Egan M., Ereshefsky L., Hodgson R.A., Hyde L.A., Jhee S., Kleijn H.J., Kuvelkar R., Li W., Mattson B.A., Mei H., Palcza J., Scott J.D., Tanen M., Troyer M.D., Tseng J.L., Stone J.A., Parker E.M., Forman M.S. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Sci. Transl. Med. 2016;8(363):363ra150. doi: 10.1126/scitranslmed.aad9704. PubMed DOI

Sakamoto K., Matsuki S., Matsuguma K., Yoshihara T., Uchida N., Azuma F., Russell M., Hughes G., Haeberlein S.B., Alexander R.C., Eketjäll S., Kugler A.R. BACE1 inhibitor lanabecestat (azd3293) in a phase 1 study of healthy japanese subjects: pharmacokinetics and effects on plasma and cerebrospinal fluid Aβ peptides. J. Clin. Pharmacol. 2017;57(11):1460–1471. doi: 10.1002/jcph.950. PubMed DOI

Lopez Lopez C., Tariot P.N., Caputo A., Langbaum J.B., Liu F., Riviere M-E., Langlois C., Rouzade-Dominguez M-L., Zalesak M., Hendrix S., Thomas R.G., Viglietta V., Lenz R., Ryan J.M., Graf A., Reiman E.M. The Alzheimer’s Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement. (N. Y.) 2019;5:216–227. doi: 10.1016/j.trci.2019.02.005. PubMed DOI PMC

Li H-W., Zhang L., Qin C. Current state of research on non-human primate models of Alzheimer’s disease. Animal. Model. Exp. Med. 2019;2(4):227–238. doi: 10.1002/ame2.12092. PubMed DOI PMC

King A. The search for better animal models of Alzheimer’s disease. Nature. 2018;559(7715):S13–S15. doi: 10.1038/d41586-018-05722-9. PubMed DOI

Neuhaus C.P. Ethical issues when modelling brain disorders innon-human primates. J. Med. Ethics. 2018;44(5):323–327. doi: 10.1136/medethics-2016-104088. PubMed DOI

Newman M., Kretzschmar D., Khan I., Chen M., Verdile G., Lardelli M. Animal Models of Alzheimer’s Disease. In: Conn P.M., editor. Animal Models for the Study of Human Disease. 2nd ed. Cambridge, Massachusetts: Academic Press; 2017. pp. 1031–1085.

Drummond E., Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol. 2017;133(2):155–175. doi: 10.1007/s00401-016-1662-x. PubMed DOI PMC

Sasaguri H., Nilsson P., Hashimoto S., Nagata K., Saito T., De Strooper B., Hardy J., Vassar R., Winblad B., Saido T.C. APP mouse models for Alzheimer’s disease preclinical studies. EMBO J. 2017;36(17):2473–2487. doi: 10.15252/embj.201797397. PubMed DOI PMC

Devi L., Ohno M. Mechanisms that lessen benefits of β-secretase reduction in a mouse model of Alzheimer’s disease. Transl. Psychiatry. 2013;3:e284–e284. doi: 10.1038/tp.2013.59. PubMed DOI PMC

Hu X., Das B., Hou H., He W., Yan R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J. Exp. Med. 2018;215(3):927–940. doi: 10.1084/jem.20171831. PubMed DOI PMC

Bennett B.D., Denis P., Haniu M., Teplow D.B., Kahn S., Louis J-C., Citron M., Vassar R. A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s β -secretase. J. Biol. Chem. 2000;275(48):37712–37717. doi: 10.1074/jbc.M005339200. PubMed DOI

Ding Y., Ko M.H., Pehar M., Kotch F., Peters N.R., Luo Y., Salamat S.M., Puglielli L. Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation. J. Biol. Chem. 2012;287(11):8424–8433. doi: 10.1074/jbc.M111.310136. PubMed DOI PMC

Mak A.B., Pehar M., Nixon A.M.L., Williams R.A., Uetrecht A.C., Puglielli L., Moffat J. Post-translational regulation of CD133 by ATase1/ATase2-mediated lysine acetylation. J. Mol. Biol. 2014;426(11):2175–2182. doi: 10.1016/j.jmb.2014.02.012. PubMed DOI PMC

John B.A., Meister M., Banning A., Tikkanen R. Flotillins bind to the dileucine sorting motif of β-site amyloid precursor protein-cleaving enzyme 1 and influence its endosomal sorting. FEBS J. 2014;281(8):2074–2087. doi: 10.1111/febs.12763. PubMed DOI

Puzzo D., Privitera L., Leznik E., Fà M., Staniszewski A., Palmeri A., Arancio O. Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 2008;28(53):14537–14545. doi: 10.1523/JNEUROSCI.2692-08.2008. PubMed DOI PMC