Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BioDrugs
Published in: BioDrugs 3/2016

01-06-2016 | Review Article

Future Therapeutics in Alzheimer’s Disease: Development Status of BACE Inhibitors

Author: Genevieve Evin

Published in: BioDrugs | Issue 3/2016

Login to get access

Abstract

Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population. AD manifests by progressive decline in cognitive functions and alterations in behaviour, which are the result of the extensive degeneration of brain neurons. The AD pathogenic mechanism involves the accumulation of amyloid beta peptide (Aβ), an aggregating protein fragment that self-associates to form neurotoxic fibrils that trigger a cascade of cellular events leading to neuronal injury and death. Researchers from academia and the pharmaceutical industry have pursued a rational approach to AD drug discovery and targeted the amyloid cascade. Schemes have been devised to prevent the overproduction and accumulation of Aβ in the brain. The extensive efforts of the past 20 years have been translated into bringing new drugs to advanced clinical trials. The most progressed mechanism-based therapies to date consist of immunological interventions to clear Aβ oligomers, and pharmacological drugs to inhibit the secretase enzymes that produce Aβ, namely β-site amyloid precursor-cleaving enzyme (BACE) and γ-secretase. After giving an update on the development and current status of new AD therapeutics, this review will focus on BACE inhibitors and, in particular, will discuss the prospects of verubecestat (MK-8931), which has reached phase III clinical trials.
Literature
1.
2.
Perl DP. Neuropathology of Alzheimer’s Disease. Mt Sinai J Med. 2010;77:32–42.
3.
4.
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985;82:4245–9.PubMedPubMedCentralCrossRef
5.
Sheng M, Sabatini BL, Südhof TC. Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol. 2012;4:pii: a005777.
6.
Benilova I, Karran E, De Strooper B. The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–57.PubMedCrossRef
7.
Iqbal K, Liu F, Gong C-X. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol. 2016;12:15–27.PubMedCrossRef
8.
Mondragón-Rodríguez S, Perry G, Zhu X, Boehm J. Amyloid beta and tau proteins as therapeutic targets for Alzheimer’s disease treatment: rethinking the current strategy. Int J Alzheimers Dis. 2012;2012:630182.PubMedPubMedCentral
9.
Mudher A, Lovestone S. Alzheimer’s disease—do tauists and baptists finally shake hands? Trends Neurosci. 2002;25:22–6.PubMedCrossRef
10.
Lonskaya I, Hebron M, Chen W, Schachter J, Moussa C. Tau deletion impairs intracellular β-amyloid-42 clearance and leads to more extracellular plaque deposition in gene transfer models. Mol Neurodegen. 2014;9:46.
11.
12.
Kovacs GG. Invited review: Neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol. 2015;41:3–23.PubMedCrossRef
13.
Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325:733–6.PubMedCrossRef
14.
Nhan HS, Chiang K, Koo EH. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol. 2015;129:1–19.PubMedPubMedCentralCrossRef
15.
Nalivaeva NN, Turner AJ. The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett. 2013;587:2046–54.
16.
17.
Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med. 2012;2012:2.
18.
Pardossi-Piquard R, Checler F. The physiology of the beta-amyloid precursor protein intracellular domain AICD. J Neurochem. 2012;120(Suppl 1):109–24.PubMedCrossRef
19.
Cao X, Sudhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001;293:115–20.PubMedCrossRef
20.
Iwatsubo T. The gamma-secretase complex: machinery for intramembrane proteolysis. Curr Opin Neurobiol. 2004;14:379–83.PubMedCrossRef
21.
Tomita T. Molecular mechanism of intramembrane proteolysis by γ-secretase. J. Biochem. 2014;156:195–201.PubMedCrossRef
22.
Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci USA. 1999;96:3922–7.PubMedPubMedCentralCrossRef
23.
Buxbaum JD, Liu KN, Luo Y, Slack JL, Stocking KL, Peschon JJ, et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998;273:27765–7.PubMedCrossRef
24.
Chami L, Checler F. BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer’s disease. Mol Neurodegen. 2012;7:52.CrossRef
25.
Tamagno E, Guglielmotto M, Monteleone D, Vercelli A, Tabaton M. Transcriptional and post-transcriptional regulation of β-secretase. IUBMB Life. 2012;64:943–50.PubMedCrossRef
26.
Tan J, Li QX, Ciccotosto G, Crouch PJ, Culvenor JG, White AR, et al. Mild oxidative stress induces redistribution of BACE1 in non-apoptotic conditions and promotes the amyloidogenic processing of Alzheimer’s disease amyloid precursor protein. PloS One. 2013;8:e61246.PubMedPubMedCentralCrossRef
27.
Baranello RJ, Bharani KL, Padmaraju V, Chopra N, Lahiri DK, Greig NH, et al. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr Alzheimer Res. 2015;12:32–46.PubMedPubMedCentralCrossRef
28.
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat Rev Mol Cell Biol. 2007;8:101–12.PubMedCrossRef
29.
Haass C, Hung AY, Schlossmacher MG, Oltersdorf T, Teplow DB, Selkoe DJ. Normal cellular processing of the β-amyloid precursor protein results in the secretion of the amyloid β peptide and related molecules. Ann N Y Acad Sci. 1993;695(1):109–16.PubMedCrossRef
30.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.PubMedCrossRef
31.
32.
Tanzi RE, Kovacs DM, Kim T-W, Moir RD, Guenette SY, Wasco W. REVIEWThe Gene Defects Responsible for Familial Alzheimer’s Disease. Neurobiol Dis. 1996;3:159–68.PubMedCrossRef
33.
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the [beta]-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature. 1992;360:672–4.PubMedCrossRef
34.
Herl L, Thomas AV, Lill CM, Banks M, Deng A, Jones PB, et al. Mutations in amyloid precursor protein affect its interactions with presenilin/γ-secretase. Mol Cell Neurosci. 2009;41:166–74.PubMedPubMedCentralCrossRef
35.
Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, et al. Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 – > Met betaAPP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci USA. 1999;96:4119–24.PubMedPubMedCentralCrossRef
36.
Czech C, Tremp G, Pradier L. Presenilins and Alzheimer’s disease: biological functions and pathogenic mechanisms. Progr Neurobiol. 2000;60:363–84.CrossRef
37.
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–9.PubMedCrossRef
38.
Lambert J-C, Amouyel P. Genetics of Alzheimer’s disease: new evidences for an old hypothesis? Curr Opin Genet Dev. 2011;21:295–301.PubMedCrossRef
39.
Kim M, Suh J, Romano D, Truong MH, Mullin K, Hooli B, et al. Potential late-onset Alzheimer’s disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity. Hum Mol Genet. 2009;18:3987–96.PubMedPubMedCentralCrossRef
40.
Lambert J-C, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat enet. 2013;45:1452–8.CrossRef
41.
Calero M, Gómez-Ramos A, Calero O, Soriano E, Avila J, Medina M. Additional mechanisms conferring genetic susceptibility to Alzheimer’s disease. Front Cell Neurosci. 2015;9:138.PubMedPubMedCentralCrossRef
42.
43.
44.
Ingram DK. Vaccine development for Alzheimer’s disease: a shot of good news. Trends Neurosci. 2001;24:305–7.PubMedCrossRef
45.
Solomon B. Immunological approaches as therapy for Alzheimer’s disease. Expert Opin Biol Ther. 2002;2:907–17.PubMedCrossRef
46.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999;400:173–7.PubMedCrossRef
47.
Serrano-Pozo A, William CM, Ferrer I, Uro-Coste E, Delisle M-B, Maurage C-A, et al. Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology. Brain. 2010;133:1312–27.PubMedPubMedCentralCrossRef
48.
Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, et al. Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64:1553–62.PubMedCrossRef
49.
50.
Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, et al. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2015;11:597–604.CrossRef
51.
Farlow MR, Andreasen N, Riviere M-E, Vostiar I, Vitaliti A, Sovago J, et al. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res Ther. 2015;7(1):23.PubMedPubMedCentralCrossRef
52.
53.
Arai H, Suzuki H, Yoshiyama T. Vanutide Cridificar and the QS-21 adjuvant in Japanese subjects with mild to moderate Alzheimer’s disease: results from two phase 2 studies. Curr Alzheimer Res. 2015;12:242–54.PubMedCrossRef
54.
Mandler M, Santic R, Gruber P, Cinar Y, Pichler D, Funke SA, et al. Tailoring the antibody response to aggregated aβ using novel alzheimer-vaccines. PLoS One. 2015;10:e0115237.PubMedPubMedCentralCrossRef
55.
56.
Bard F, Cannon C, Barbour R, Burke R-L, Games D, Grajeda H, et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med. 2000;6:916–9.PubMedCrossRef
57.
DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2001;98:8850–5.PubMedPubMedCentralCrossRef
58.
Dodart J-C, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, et al. Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer’s disease model. Nat Neurosci. 2002;5:452–7.PubMed
59.
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–70.PubMedPubMedCentralCrossRef
60.
Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9:363–72.PubMedCrossRef
61.
Blennow K, Zetterberg H, Rinne JO, et al. EFfect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate alzheimer disease. Arch Neurol. 2012;69:1002–10.PubMedCrossRef
62.
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33.PubMedPubMedCentralCrossRef
63.
Liu E, Schmidt ME, Margolin R, Sperling R, Koeppe R, Mason NS, Klunk WE, Mathis CA, Salloway S, Fox NC, Hill DL, Les AS, Collins P, Gregg KM, Di J, Lu Y, Tudor IC, Wyman BT, Booth K, Broome S, Yuen E, Grundman M, Brashear HR, Bapineuzumab 301 and 302 Clinical Trial Investigators. Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials. Neurology. 2015;85:692–700.PubMedPubMedCentralCrossRef
64.
Busche MA, Grienberger C, Keskin AD, Song B, Neumann U, Staufenbiel M, et al. Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models. Nat Neurosci. 2015;18:1725–7.PubMedCrossRef
65.
Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012;8:261–71.PubMedCrossRef
66.
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. Phase 3 Trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:311–21.PubMedCrossRef
67.
Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2015;pii: S1552-5260:02148-2.
68.
Gandy S, Sano M. Alzheimer disease: Solanezumab: prospects for meaningful interventions in AD? Nat Rev Neurol. 2015;11:669–70.PubMedCrossRef
69.
Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique Aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci. 2012;32:9677–89.PubMedCrossRef
70.
Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with alzheimer disease treated with gantenerumab. Arch Neurol. 2012;69:198–207.PubMedCrossRef
71.
72.
73.
Evin G, Cappai R, Li QX, Culvenor JG, Small DH, Beyreuther K, et al. Candidate gamma-secretases in the generation of the carboxyl terminus of the Alzheimer’s disease beta A4 amyloid: possible involvement of cathepsin D. Biochemistry. 1995;34:14185–92.PubMedCrossRef
74.
Higaki J, Catalano R, Guzzetta AW, Quon D, Navé J-F, Tarnus C, et al. Processing of β-amyloid precursor protein by cathepsin D. J Biol Chem. 1996;271:31885–93.PubMedCrossRef
75.
Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, et al. L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry. 2000;39:8698–704.PubMedCrossRef
76.
Wolfe MS, Citron M, Diehl TS, Xia W, Donkor IO, Selkoe DJ. A substrate-based difluoro ketone selectively inhibits Alzheimer’s gamma-secretase activity. J Med Chem. 1998;41:6–9.PubMedCrossRef
77.
Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, et al. Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate. Proc Natl Acad Sci USA. 2002;5(99):2720–5.CrossRef
78.
Tian G, Sobotka-Briner CD, Zysk J, Liu X, Birr C, Sylvester MA, et al. Linear non-competitive inhibition of solubilized human gamma-secretase by pepstatin A methylester, L685458, sulfonamides, and benzodiazepines. J Biol Chem. 2002;277:31499–505.PubMedCrossRef
79.
Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, et al. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000;405:689–94.PubMedCrossRef
80.
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999;398:513–7.PubMedCrossRef
81.
Evin G, Sharples RA, Weidemann A, Reinhard FB, Carbone V, Culvenor JG, et al. Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer’s disease. Biochemistry. 2001;40:8359–68.PubMedCrossRef
82.
Seiffert D, Bradley JD, Rominger CM, Rominger DH, Yang F, Meredith JE, et al. Presenilin-1 and -2 are molecular targets for γ-secretase inhibitors. J Biol Chem. 2000;275:34086–91.PubMedCrossRef
83.
Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001;76:173–81.PubMedCrossRef
84.
De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398:518–22.PubMedCrossRef
85.
86.
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279:12876–82.PubMedCrossRef
87.
Henley DB, May PC, Dean RA, Siemers ER. Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer’s disease. Expert Opin Pharmacother. 2009;10:1657–64.PubMedCrossRef
88.
Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, et al. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol. 2009;66:48–54.PubMedPubMedCentralCrossRef
89.
Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, et al. Phase II safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer’s disease. Arch Neurol. 2008;65:1031–8.PubMedPubMedCentralCrossRef
90.
Gillman KW, Starrett JE, Parker MF, Xie K, Bronson JJ, Marcin LR, et al. Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med Chem Lett. 2010;1:120–4.PubMedPubMedCentralCrossRef
91.
Albright CF, Dockens RC, Meredith JE, Olson RE, Slemmon R, Lentz KA, et al. Pharmacodynamics of selective inhibition of γ-secretase by avagacestat. J Pharmacol Exp Ther. 2013;344:686–95.PubMedCrossRef
92.
Tong G, Wang J-S, Sverdlov O, Huang S-P, Slemmon R, Croop R, et al. Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral γ-secretase inhibitor BMS-708163 (avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther. 2012;34:654–67.PubMedCrossRef
93.
Tong G, Wang J-S, Sverdlov O, Huang S-P, Slemmon R, Croop R, et al. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the γ-secretase inhibitor avagacestat. Br J Clin Pharmacol. 2013;75(1):136–45.PubMedPubMedCentralCrossRef
94.
Coric V, van Dyck CH, Salloway S, et al. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate alzheimer disease. Arch Neurol. 2012;69:1430–40.PubMedCrossRef
95.
Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72:1324–33.PubMedCrossRef
96.
Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, et al. Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein γ-secretase for the treatment of Alzheimer’s disease. J Pharmacol Exp Ther. 2009;331:598–608.PubMedCrossRef
97.
Niva C, Parkinson J, Olsson F, van Schaick E, Lundkvist J, Visser SG. Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data. Eur J Clin Pharmacol. 2013;69:1247–60.PubMedCrossRef
98.
Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, et al. Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease. J Exp Med. 2015;212:2003–13.PubMedPubMedCentralCrossRef
99.
Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, et al. The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012;31:2261–74.PubMedPubMedCentralCrossRef
100.
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic A[beta]42 independently of cyclooxygenase activity. Nature. 2001;414:212–6.PubMedCrossRef
101.
Green RC, Schneider LS, Amato DA, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild alzheimer disease: a randomized controlled trial. JAMA. 2009;302:2557–64.PubMedPubMedCentralCrossRef
102.
Takagi-Niidome S, Sasaki T, Osawa S, Sato T, Morishima K, Cai T, et al. Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase. J Neurosci. 2015;35:2646–56.PubMedCrossRef
103.
X-c Bai, Yan C, Yang G, Lu P, Ma D, Sun L, et al. An atomic structure of human γ-secretase. Nature. 2015;525:212–7.CrossRef
104.
Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, et al. TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature. 2006;440:1208–12.PubMedCrossRef
105.
Wang J, Lu R, Yang J, Li H, He Z, Jing N, et al. TRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production. Nat Commun. 2015;6:8876.PubMedPubMedCentralCrossRef
106.
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, et al. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature. 2010;467:95–8.PubMedPubMedCentralCrossRef
107.
Hussain I, Fabrègue J, Anderes L, Ousson S, Borlat F, Eligert V, et al. The role of γ-secretase activating protein (GSAP) and imatinib in the regulation of γ-secretase activity and amyloid-β generation. J Biol Chem. 2013;288:2521–31.PubMedPubMedCentralCrossRef
108.
De Strooper B. Chávez Gutiérrez L. Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer’s disease and beyond. Annu Rev Pharmacol Toxicol. 2015;55:419–37.PubMedCrossRef
109.
110.
Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, et al. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet. 2001;10:1317–24.PubMedCrossRef
111.
Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, et al. Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci. 2001;4:231–2.PubMedCrossRef
112.
Zhao J, Fu Y, Yasvoina M, Shao P, Hitt B, O’Connor T, et al. β-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer’s disease pathogenesis. J Neurosci. 2007;27:3639–49.PubMedCrossRef
113.
Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G. Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol. 2002;51:783–6.PubMedCrossRef
114.
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol. 2002;59:1381–9.PubMedCrossRef
115.
Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, et al. Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci USA. 2004;101:3632–7.PubMedPubMedCentralCrossRef
116.
Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh A, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000;290:150–3.PubMedCrossRef
117.
Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci USA. 2000;97:9712–7.PubMedPubMedCentralCrossRef
118.
Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, et al. The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the Down critical region. FEBS Lett. 2000;468:59–64.PubMedCrossRef
119.
Saunders AJ, Kim T-W, Tanzi RE. BACE Maps to Chromosome 11 and a BACE homolog, BACE2, reside in the obligate Down syndrome region of chromosome 21. Science. 1999;286:1255.CrossRef
120.
Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, et al. ASP1 (BACE2) cleaves the amyloid precursor protein at the β-secretase site. Mol Cell Neurosci. 2000;16:609–19.PubMedCrossRef
121.
Fluhrer R, Capell A, Westmeyer G, Willem M, Hartung B, Condron MM, et al. A non-amyloidogenic function of BACE-2 in the secretory pathway. J Neurochem. 2002;81:1011–20.PubMedCrossRef
122.
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;276:36788–96.PubMedCrossRef
123.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735–41.PubMedCrossRef
124.
Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, et al. Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem. 2000;275:20647–51.PubMedCrossRef
125.
Esterházy D, Stützer I, Wang H, Rechsteiner Markus P, Beauchamp J, Döbeli H, et al. Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell Metabol. 2011;14:365–77.CrossRef
126.
Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci USA. 2013;110:10658–63.PubMedPubMedCentralCrossRef
127.
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;288:10536–47.PubMedPubMedCentralCrossRef
128.
Evin G, Lessene G, Wilkins S. BACE inhibitors as potential drugs for the treatment of Alzheimer’s disease: focus on bioactivity. Recent Pat CNS Drug Discov. 2011;6:91–106.PubMedCrossRef
129.
Evin G, Kenche VB. BACE inhibitors as potential therapeutics for Alzheimer’s disease. Recent Pat CNS Drug Discov. 2007;2:188–99.PubMedCrossRef
130.
131.
Park H, Lee S. Determination of the active site protonation state of β-secretase from molecular dynamics simulation and docking experiment: implications for structure-based inhibitor design. J Am Chem Soc. 2003;125:16416–22.PubMedCrossRef
132.
McGaughey GB, Holloway MK. Structure-guided design of β-secretase (BACE-1) inhibitors. Expert Opin Drug Discov. 2007;2:1129–38.PubMedCrossRef
133.
Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, et al. Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases β-cleavage of amyloid precursor protein and amyloid-beta production in vivo. J Neurochem. 2007;100:802–9.PubMedCrossRef
134.
Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu X, Chang W, et al. Design, synthesis, and X-ray structure of potent memapsin 2 (β-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. J Med Chem. 2007;17(50):2399–407.CrossRef
135.
Yu J, Koelsch G, Li A, Turner RT, Bilcer GM, Grove C, et al. In vivo efficacy of BACE-1 inhibitor CTS21166 (ASP1702) in rat CNS compartments. Alzheimers Dement. 2009;5:P430–1.CrossRef
136.
Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, et al. Beta-secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice. FASEB J. 2011;25:775–84.PubMedPubMedCentralCrossRef
137.
Oehlrich D, Prokopcova H, Gijsen HJM. The evolution of amidine-based brain penetrant BACE1 inhibitors. Bioorg Med Chem Lett. 2014;24:2033–45.PubMedCrossRef
138.
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011;31:16507–16.PubMedCrossRef
139.
May P, Boggs L, Brier R, Calligaro D, Citron M, Day T, et al. Preclinical characterization of LY2886721: A BACE1 inhibitor in clinical development for early Alzheimer’s disease. Alzheimers Dement. 2012;8:P95.CrossRef
140.
May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, et al. The potent BACE1 inhibitor LY2886721 elicits robust central aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci. 2015;35:1199–210.PubMedCrossRef
141.
Jeppsson F, Eketjall S, Janson J, Karlstrom S, Gustavsson S, Olsson L-L, et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem. 2012;287:41245–57.PubMedPubMedCentralCrossRef
142.
Quartino A, Huledal G, Sparve E, Lüttgen M, Bueters T, Karlsson P, et al. Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers. Clin Pharmacol Drug Dev. 2014;3:396–405.PubMedCrossRef
143.
Sparve E, Quartino AL, Lüttgen M, Tunblad K, Gårdlund AT, Fälting J, et al. Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839. J Pharmacol Exp Therapeut. 2014;350:469–78.CrossRef
144.
145.
Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, et al. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid β-peptides. Bioorg Med Chem Lett. 2013;23:5300–6.PubMedCrossRef
146.
Neumann U, Rueeger H, Machauer R, Veenstra S, Lueoend R, Tintelnot-Blomley M, et al. A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice. Mol Neurodegener. 2015;10:44.PubMedPubMedCentralCrossRef
147.
Hyde L, Chen X, Stahl L, Sondey M, Scott J, Cumming J, et al. Chronic BACE inhibition dramatically slows the rate of Aβ accumulation and the development of amyloid plaques in young TgCRND8 mice. Alzheimers Dement. 2012;8:P188.
148.
Kennedy M, Scott J, Cantu C, Chen X, Kuvelkar R, Werner B, et al. Preclinical profile of MK-8931, a structurally novel, centrally-active, β-secretase (BACE1) inhibitor for the treatment of Alzheimer’s disease. 12th International Conference AD/PD, Nice, France, March 18–22, 2015. Neurodegen Dis. 2015;15(Suppl. 1):290.
149.
Forman M, Tseng J, Palcza J, Leempoels J, Ramael S, Krishna G, et al. The novel BACE inhibitor MK-8931 dramatically lowers CSF Aβ peptides in healthy subjects: results from a rising single dose study (PL02.004). Neurol. 2012;78:PL02.004.CrossRef
150.
Forman M, Palcza J, Tseng J, Leempoels J, Ramael S, Han D, et al. The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single- and multiple-dose administration. Alzheimers Dementia. 2012;8:P704.CrossRef
151.
Forman M, Kleijn H-J, Dockendorf M, Palcza J, Tseng J, Canales C, et al. The novel BACE inhibitor MK-8931 dramatically lowers CSF β-amyloid in patients with mild-to-moderate Alzheimer’s disease. Alzheimers Dement. 2013;9:P139.CrossRef
152.
Stone J, Kleijn HJ, Dockendorf M, Ma L, Palcza J, Tseng J, et al. Consistency of BACE inhibitor-mediated brain amyloid production inhibition by MK-8931 in Alzheimer’s disease patients and healthy young adults. Alzheimers Dement. 2013;9:P690–1.CrossRef
153.
Min K, Forman M, Dockendorf M, Palcza J, Soni P, Ma L, et al. A study to evaluate the pharmacokinetics and pharmacodynamics of single and multiple oral doses of the novel BACE inhibitor MK-8931 in Japanese subjects. Alzheimers Dement. 2012;8:P186.CrossRef
154.
Haeberlein SB, Cebers G, Höglund K, Salter H, Eketjäll S, Bogstedt A, et al. AZD3293, a potent and selective orally active, brain-permeable BACE1 inhibitor. Alzheimers Dement. 2013;9:P813.CrossRef
155.
Eketjäll SJJ, Kaspersson K, Bogstedt A, Jeppsson F, Fälting J, Haeberlein SB, Kugler AR, Alexander RC, Cebers G. AZD3293: A novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J Alzheimers Dis. 2016;40:1109–23.CrossRef
156.
Höglund K, Salter H, Zetterberg H, Andreason U, Olsson T, Alexander R, et al. Monitoring the soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ) fragments in plasma and CSF from healthy individuals treated with BACE inhibitor AZD3293 in a multiple ascending dose study: pharmacokinetic and pharmacodynamic correlate. Alzheimers Dement. 2014;10:P447.CrossRef
157.
Alexander R, Budd S, Russell M, Kugler A, Cebers G, Ye N, et al. AZD3293 A novel BACE1 inhibitor: safety, tolerability, and effects on plasma and CSF Aβ peptides following single- and multiple-dose administration. Neurobiol Aging. 2014;35(Supplement 1):S2.CrossRef
158.
159.
Fukushima T, Osada Y, Ishibashi A, Lucas F. Novel BACE1 inhibitor, E2609, lowers Abeta levels in the brain, cerebrospinal fluid and plasma in rats and guinea pigs. Alzheimers Dement. 2012;8:P223–4.CrossRef
160.
Lai R, Albala B, Kaplow JM, Aluri J, Yen M, Satlin A. First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma β-amyloid levels after single dosing. Alzheimers Dement. 2012;8:P96.CrossRef
161.
Albala B, Kaplow JM, 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. 2013;8:S743.CrossRef
162.
Bernier F, Sato Y, Matijevic M, Desmond H, McGrath S, Burns L, et al. Clinical study of E2609, a novel BACE1 inhibitor, demonstrates target engagement and inhibition of BACE1 activity in CSF. Alzheimers Dement. 2013;9:P886.CrossRef
163.
Timmers M, Van Broeck B, Slemmon J, et al. Profiling the dynamics of CSF and plasma Aβ reduction with JNJ-54861911, an oral BACE inhibitor. In: 12th international conference on Alzheimer’s and Parkinson’s diseases and related neurological disorders (AD/PD) Nice (France) Mar 2015.
164.
Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Camacho IE, Marjaux E, Craessaerts K, Roebroek AJ, Schwake M, D’Hooge R, Bach P, Kalinke U, Moechars D, Alzheimer C, Reiss K, Saftig P, De Strooper B. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem. 2005;280:30797–806.PubMedCrossRef
165.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the β-secretase BACE1. Science. 2006;314:664–6.PubMedCrossRef
166.
Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9:1520–5.PubMedCrossRef
167.
Hu X, Hu J, Dai L, Trapp B, Yan R. Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves. J Neurosci. 2015;35:3806–14.PubMedPubMedCentralCrossRef
168.
Savonenko AV, Melnikova T, Laird FM, Stewart KA, Price DL, Wong PC. Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proc Natl Acad Sci USA. 2008;105:5585–90.PubMedPubMedCentralCrossRef
169.
Cheret C, Willem M, Fricker FR, Wende H, Wulf-Goldenberg A, Tahirovic S, et al. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 2013;32:2015–28.PubMedPubMedCentralCrossRef
170.
Kim D, Carey B, Wang H, Ingano L, Binshtok A, Wertz M, et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol. 2007;9:755–64.PubMedPubMedCentralCrossRef
171.
Zhou L, Barao S, Laga M, Bockstael K, Borgers M, Gijsen H, et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem. 2012;287(31):25927–40.PubMedPubMedCentralCrossRef
172.
Kuhn P-H, Koroniak K, Hogl S, Colombo A, Zeitschel U, Willem M, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012;31:3157–68.PubMedPubMedCentralCrossRef
173.
Cai J, Qi X, Kociok N, Skosyrski S, Emilio A, Ruan Q, et al. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med. 2012;4:980–91.PubMedPubMedCentralCrossRef
174.
Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci USA. 2013;110:10658–63.PubMedPubMedCentralCrossRef
175.
Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, et al. eta-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015;526:443–7.PubMedCrossRef
176.
Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier JM, et al. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer’s disease. Cell Mol Life Sci. 2016;73:217–36.PubMedPubMedCentralCrossRef
177.
Blennow K. The past and the future of Alzheimer’s disease CSF biomarkers—a journey towards validated biochemical tests covering the whole spectra of molecular events. Front Neurosci. 2015;9:345.PubMedPubMedCentralCrossRef
178.
Snyder PJ, Kahle-Wrobleski K, Brannan S, Miller DS, Schindler RJ, DeSanti S, et al. Assessing cognition and function in Alzheimer’s disease clinical trials: do we have the right tools? Alzheimers Dement. 2014;10:853–60.PubMedCrossRef
179.
Lim YY, Maruff P, Pietrzak RH, Ellis KA, Darby D, Ames D, et al. Aβ; and cognitive change: examining the preclinical and prodromal stages of Alzheimer’s disease. Alzheimers Dement. 2014;10:743–51.PubMedCrossRef
180.
181.
182.
183.
Lauritzen I, Pardossi-Piquard R, Bauer C, Brigham E, Abraham J-D, Ranaldi S, et al. The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci. 2012;32:16243–55.PubMedCrossRef
184.
Kandalepas PC, Sadleir KR, Eimer WA, Zhao J, Nicholson DA, Vassar R. The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol. 2013;126:329–52.PubMedPubMedCentralCrossRef
185.
Castillo-Carranza DL, Gerson JE, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Kayed R. Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis. 2014;40(Suppl 1):S97–111.PubMed
186.
187.
Georgievska B, Sandin J, Doherty J, Mörtberg A, Neelissen J, Andersson A, et al. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J Neurochem. 2013;125:446–56.PubMedCrossRef
188.
Miguel M, Jesus A. Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimers disease. Curr Pharm Des. 2010;16:2790–8.CrossRef
189.
Llorens-Martin M, Jurado J, Hernandez F, Avila J. GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci. 2014;7:46.PubMed
190.
Ly PTT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, et al. Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J Clin Invest. 2013;123(1):224–35.PubMedPubMedCentralCrossRef
191.
Di Martino RMC, De Simone A, Andrisano V, Bisignano P, Bisi A, Gobbi S, et al. Versatility of the curcumin scaffold: discovery of potent and balanced dual BACE-1 and GSK-3β inhibitors. J Med Chem. 2016;59:531–44.PubMedCrossRef
192.
Prati F, De Simone A, Armirotti A, Summa M, Pizzirani D, Scarpelli R, et al. 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3β fragment hits against Alzheimer’s disease. ACS Chem Neurosci. 2015;6:1665–82.PubMedCrossRef
Metadata
Title
Future Therapeutics in Alzheimer’s Disease: Development Status of BACE Inhibitors
Author
Genevieve Evin
Publication date
01-06-2016
Publisher
Springer International Publishing
Published in
BioDrugs / Issue 3/2016
Print ISSN: 1173-8804
Electronic ISSN: 1179-190X
DOI
https://doi.org/10.1007/s40259-016-0168-3

Other articles of this Issue 3/2016

BioDrugs 3/2016 Go to the issue

Adis Drug Evaluation

Shingles (Herpes Zoster) Vaccine (Zostavax®): A Review in the Prevention of Herpes Zoster and Postherpetic Neuralgia

Short Communication

Comparability of Antibody-Mediated Cell Killing Activity Between a Proposed Biosimilar RTXM83 and the Originator Rituximab

Review Article

Update on Metastatic Uveal Melanoma: Progress and Challenges

Original Research Article

Identification of Low-Level Product-Related Variants in Filgrastim Products Presently Available in Highly Regulated Markets

Review Article

Assessing the Immunogenicity of Biopharmaceuticals

Short Communication

Anagrelide and Mutational Status in Essential Thrombocythemia