993
Views
84
CrossRef citations to date
0
Altmetric
Review

Investigational BACE inhibitors for the treatment of Alzheimer’s disease

&
Pages 967-975 | Received 03 Sep 2019, Accepted 17 Oct 2019, Published online: 29 Oct 2019

References

  • Brookmeyer R, Corrada MM, Curriero FC, et al. Survival following a diagnosis of Alzheimer disease. Arch Neurol. 2002;59(11):1764–1767.
  • Jansen IE, Savage JE, Watanabe K, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51:404–413.
  • Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature. 2012;488:96–99.
  • Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS β-amyloid in Alzheimer’s disease. Science. 2010;330:1774.
  • Yang LB, Lindholm K, Yan R, et al. Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med. 2003;9:3–4.
  • Liu CC, Liu CC, Kanekiyo T, et al. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9:106–118.
  • Kandalepas PC, Sadleir KR, Eimer WA, et al. The Alzheimer’s β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol. 2013;126:329–352.
  • Yan R, Vassar R. Targeting the β-secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol. 2014;13:319–329.
  • Ghosh AK, Brindisi M, Yen YC, et al. Highly selective and potent human β-secretase 2 (BACE2) inhibitors against type 2 diabetes: design, synthesis, X-ray structure and structure-activity relationship studies. ChemMedChem. 2019;14:545–560.
  • Meakin PJ, Harper AJ, Hamilton DL, et al. Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice. Biochem J. 2012;441:285–296.
  • Plucińska K, Dekeryte R, Koss D, et al. Neuronal human BACE1 knockin induces systemic diabetes in mice. Diabetologia. 2016;59:1513–1523.
  • Coimbra JRM, Marques DFF, Baptista SJ, et al. Highlights in BACE1 inhibitors for Alzheimer’s disease treatment. Front Chem. 2018;6:178.
  • Fukumoto H, Takahashi H, Tarui N, et al. A noncompetitive BACE1 inhibitor TAK-070 ameliorates Aβ pathology and behavioral deficits in a mouse model of Alzheimer’s disease. J Neurosci. 2010;30:11157–11166.
  • Thakker DR, Sankaranarayanan S, Weatherspoon MR, et al. Centrally delivered BACE1 inhibitor activates microglia, and reverses amyloid pathology and cognitive deficit in aged Tg2576 mice. J Neurosci. 2015;35:6931–6936.
  • Keskin AD, Kekuš M, Adelsberger H, et al. BACE inhibition-dependent repair of Alzheimer’s pathophysiology. Proc Natl Acad Sci U S A. 2017;114:8631–8636.
  • Panza F, Lozupone M, Logroscino G, et al. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15:73–88.
  • Cole SL, Vassar R. The Alzheimer’s disease β-secretase enzyme, BACE1. Mol Neurodegener. 2007;2:22.
  • Laird FM, Cai H, Savonenko AV, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci. 2005;25:11693–11709.
  • 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;6:78–84.
  • Plucińska K, Crouch B, Koss D, et al. Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci. 2014;34:10710–10728.
  • Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2018;378:1691–1703.
  • Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380:1408–1420.
  • Henley D, Raghavan N, Sperling R, et al. preliminary results of a trial of atabecestat in preclinical Alzheimer’s disease. N Engl J Med. 2019;380:1483–1485.
  • Strobel G. BACE inhibitors: postmortem on one, live updates on two. Alzheimer Res Forum. 2019 May;17.
  • Lo AC, Duggan Evans C, Mancini M, et al. Results from the phase 2 NAVIGATE-AD clinical trial evaluating LY3202626 BACE inhibitor in patients with mild Alzheimer’s disease dementia. J Prev Alzheimers Dis. 2018;5(Suppl 1):S37.
  • Shugart J, Strobel G. Cognitive decline trips up API trials of BACE inhibitor. Alzheimer Res Forum. 2019 July;12.
  • Lynch SY, Kaplow J, Zhao J. et al. 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 Dementia. 2018;14(Suppl):P1623.
  • Caouette D Eisai and Biogen to discontinue phase III clinical studies of BACE inhibitor elenbecestat in early Alzheimer’s disease. Eisai’s press release;2019 Sept 13.
  • Yan R. Physiological functions of the β-Site amyloid precursor protein cleaving enzyme 1 and 2. Front Mol Neurosci. 2017;10:97.
  • Zhu K, Peters F, Filser S, et al. Consequences of pharmacological BACE inhibition on synaptic structure and function. Biol Psychiatry. 2018;84:478–487.
  • Zhu K, Xiang X, Filser S, et al. Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol Psychiatry. 2018;83:428–437.
  • Hitt B, Riordan SM, Kukreja L, et al. β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem. 2012;287:38408–38425.
  • Hu X, Fan Q, Hou H, et al. Neurological dysfunctions associated with altered BACE1-dependent neuregulin-1 signaling. J Neurochem. 2016;136:234–249.
  • Vassar R, Kuhn PH, Haass C, et al. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem. 2014;130:4–28.
  • Filser S, Ovsepian SV, Masana M, et al. Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biol Psychiatry. 2015;77:729–739.
  • Neumann U, Ufer M, Jacobson LH, et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol Med. 2018;10(11):e9316.
  • Doody RS, Raman R, Farlow M, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–350.
  • Bateman RJ, Siemers ER, Mawuenyega KG, et al. A γ-secretase inhibitor decreases amyloid-β production in the central nervous system. Ann Neurol. 2009;66:48–54.
  • 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;69:1430–1440.
  • 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;302:2557–2564.
  • Vandenberghe R, Riviere ME, Caputo A, et al. Active Aβ immunotherapy CAD106 in Alzheimer’s disease: a phase 2b study. Alzheimers Dement. 2016;3:10–22.
  • Schneeberger A, Hendrix S, Mandler M, et al. Results from a phase II study to assess the clinical and immunological activity of AFFITOPE® AD02 in patients with early Alzheimer’s disease. J Prev Alzheimers Dis. 2015;2:103–114.
  • Salloway S, Sperling R, Keren R, et al. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77:1253–1262.
  • Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72:1324–1333.
  • Kwart D, Gregg A, Scheckel C, et al. A large panel of isogenic APP and PSEN1 mutant human iPSC neurons reveals shared endosomal abnormalities Mediated by APP β-CTFs, not Aβ. Neuron. 2019 Aug 12. pii: S0896-6273(19)30636-1. doi: 10.1016/j.neuron.2019.07.010. [Epub ahead of print].
  • Bishop GM, Robinson SR. Physiological roles of amyloid-β and implications for its removal in Alzheimer’s disease. Drugs Aging. 2004;21:621–630.
  • Puzzo D, Gulisano W, Arancio O, et al. The keystone of Alzheimer pathogenesis might be sought in Aβ physiology. Neuroscience. 2015;307:26–36.
  • Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron. 2003;37:925–937.
  • Esteban JA. Living with the enemy: a physiological role for the β-amyloid peptide. Trends Neurosci. 2004;27:1–3.
  • Parihar MS, Brewer GJ. Amyloid-β as a modulator of synaptic plasticity. J Alzheimers Dis. 2010;22:741–763.
  • Puzzo D, Privitera L, Fà M, et al. Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Ann Neurol. 2011;69:819–830.
  • Lawrence JL, Tong M, Alfulaij N, et al. Regulation of presynaptic Ca2+, synaptic plasticity and contextual fear conditioning by a N-terminal β-amyloid fragment. J Neurosci. 2014;34:14210–14218.
  • Palmeri A, Ricciarelli R, Gulisano W, et al. Amyloid-β peptide is needed for cGMP-induced long-term potentiation and memory. J Neurosci. 2017;37:6926–6937.
  • Abramov E, Dolev I, Fogel H, et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci. 2009;12:1567–1576.
  • Morley JE, Farr SA, Banks WA, et al. A physiological role for amyloid-β protein: enhancement of learning and memory. J Alzheimers Dis. 2010;19:441–449.
  • López-Toledano MA, Shelanski ML. Neurogenic effect of β-amyloid peptide in the development of neural stem cells. J Neurosci. 2004;24:5439–5444.
  • Plant LD, Boyle JP, Smith IF, et al. The production of amyloid β peptide is a critical requirement for the viability of central neurons. J Neurosci. 2003;23:5531–5535.
  • Sun L, Zhou R, Yang G, et al. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017;114:E476–85.
  • Kepp KP. Alzheimer’s disease due to loss of function: a new synthesis of the available data. Prog Neurobiol. 2016;143:36–60.
  • Cummings JL, Tong G, Ballard C. Treatment combinations for Alzheimer’s disease: current and future pharmacotherapy options. J Alzheimers Dis. 2019;67:779–794.
  • McDade E, Bateman RJ. Stop Alzheimer’s before it starts. Nature. 2017;547:153–155.
  • Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 2018;14:653–666.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.