Targeting the β secretase BACE1 for Alzheimer's disease therapy

The Lancet Neurology

Volumn 13, Issue 3, 2014, Pages 319-329

  Yan, Riqiang ^a   Vassar, Robert ^b  

^a LERNER RESEARCH INSTITUTE   (United States)

^b NORTHWESTERN UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALZHEIMER DISEASE; AMYLOID PRECURSOR PROTEIN SECRETASES; ANIMALS; ASPARTIC ACID ENDOPEPTIDASES; CRYSTALLOGRAPHY, X-RAY; DRUG DELIVERY SYSTEMS; ENZYME INHIBITORS; HUMANS;

EID: 84894090892     PISSN: 14744422     EISSN: 14744465     Source Type: Journal    
DOI: 10.1016/S1474-4422(13)70276-X     Document Type: Review

References (85)

1. Hardy J, Selkoe DJ The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297:353-356.
2. Vassar R, Kovacs DM, Yan R, Wong PC The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 2009, 29:12787-12794.
3. Sisodia SS, St George-Hyslop PH gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?. Nat Rev Neurosci 2002, 3:281-290.
4. De Strooper B, Vassar R, Golde T The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010, 6:99-107.
5. Goldstein JL, Brown MS The LDL receptor. Arterioscler Thromb Vasc Biol 2009, 29:431-438.
6. Tanzi RE The genetics of Alzheimer disease. Cold Spring Harb Perspect Med 2012, 2:a006296.
7. Mullan M, Crawford F, Axelman K, et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1992, 1:345-347.
8. Di Fede G, Catania M, Morbin M, et al. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science 2009, 323:1473-1477.
9. Kuhn PH, Wang H, Dislich B, et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J 2010, 29:3020-3032.
10. Suh J, Choi SH, Romano DM, et al. ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function. Neuron 2013, 80:385-401.
11. 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.
12. Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286:735-741.
13. Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 1999, 402:533-537.
14. Sinha S, Anderson JP, Barbour R, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999, 402:537-540.
15. Hussain I, Powell D, Howlett DR, et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci 1999, 14:419-427.
16. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci USA 2000, 97:1456-1460.
17. Kuhn PH, Koroniak K, Hogl S, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J 2012, 31:3157-3168.
18. Bennett BD, Babu-Khan S, Loeloff R, et al. Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem 2000, 275:20647-20651.
19. Laird FM, Cai H, Savonenko AV, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005, 25:11693-11709.
20. 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, 97:9712-9717.
21. Yan R, Munzner JB, Shuck ME, Bienkowski MJ BACE2 functions as an alternative alpha-secretase in cells. J Biol Chem 2001, 276:34019-34027.
22. Fluhrer R, Capell A, Westmeyer G, et al. A non-amyloidogenic function of BACE-2 in the secretory pathway. J Neurochem 2002, 81:1011-1020.
23. Basi G, Frigon N, Barbour R, et al. Antagonistic effects of beta-site amyloid precursor protein-cleaving enzymes 1 and 2 on beta-amyloid peptide production in cells. J Biol Chem 2003, 278:31512-31520.
24. Luo Y, Bolon B, Kahn S, et al. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci 2001, 4:231-232.
25. Roberds SL, Anderson J, Basi G, 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, 10:1317-1324.
26. Cai H, Wang Y, McCarthy D, et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001, 4:233-234.
27. Dominguez D, Tournoy J, Hartmann D, et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem 2005, 280:30797-30806.
28. Ohno M, Sametsky EA, Younkin LH, et al. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 2004, 41:27-33.
29. Luo Y, Bolon B, Damore MA, et al. BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol Dis 2003, 14:81-88.
30. Ohno M, Cole SL, Yasvoina M, et al. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 2007, 26:134-145.
31. McConlogue L, Buttini M, Anderson JP, et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem 2007, 282:26326-26334.
32. 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, 126:329-352.
33. Deng M, He W, Tan Y, et al. 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, 288:30236-30245.
34. Rajapaksha TW, Eimer WA, Bozza TC, Vassar R The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb. Mol Neurodegener 2011, 6:88.
35. Cao L, Rickenbacher GT, Rodriguez S, Moulia TW, Albers MW The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease. Sci Rep 2012, 2:231.
36. Hitt B, Riordan SM, Kukreja L, Eimer WA, Rajapaksha TW, Vassar R 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.
37. Willem M, Garratt AN, Novak B, et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 2006, 314:664-666.
38. Hu X, Hicks CW, He W, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006, 9:1520-1525.
39. Hu X, He W, Diaconu C, et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB J 2008, 22:2970-2980.
40. Kobayashi D, Zeller M, Cole T, et al. BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease. Neurobiol Aging 2008, 29:861-873.
41. Ohno M, Chang L, Tseng W, et al. Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 2006, 23:251-260.
42. Cheret C, Willem M, Fricker FR, et al. Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J 2013, 32:2015-2028.
43. Harrison SM, Harper AJ, Hawkins J, et al. BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol Cell Neurosci 2003, 24:646-655.
44. Hu X, He W, Luo X, Tsubota KE, Yan R BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep 2013, 4:40-49.
45. Hu X, Zhou X, He W, et al. BACE1 deficiency causes altered neuronal activity and neurodegeneration. J Neurosci 2010, 30:8819-8829.
46. 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, 105:5585-5590.
47. Cai J, Qi X, Kociok N, et al. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol Med 2012, 4:980-991.
48. Hitt BD, Jaramillo TC, Chetkovich DM, Vassar R BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization. Mol Neurodegener 2010, 5:31.
49. 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.
50. Hoffmeister A, Tuennemann J, Sommerer I, et al. Genetic and biochemical evidence for a functional role of BACE1 in the regulation of insulin mRNA expression. Obesity (Silver Spring) 2013, 21:626-633.
51. Kim DY, Carey BW, Wang H, et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat Cell Biol 2007, 9:755-764.
52. Esterházy D, Stützer I, Wang H, et al. Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell Metab 2011, 14:365-377.
53. Rochin L, Hurbain I, Serneels L, et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci USA 2013, 110:10658-10663.
54. Zhou L, Barão S, Laga M, et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem 2012, 287:25927-25940.
55. Fleck D, van Bebber F, Colombo A, et al. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J Neurosci 2013, 33:7856-7869.
56. Luo X, Prior M, He W, et al. Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination. J Biol Chem 2011, 286:23967-23974.
57. Heyden A, Angenstein F, Sallaz M, Seidenbecher C, Montag D Abnormal axonal guidance and brain anatomy in mouse mutants for the cell recognition molecules close homolog of L1 and NgCAM-related cell adhesion molecule. Neuroscience 2008, 155:221-233.
58. Montag-Sallaz M, Schachner M, Montag D Misguided axonal projections, neural cell adhesion molecule 180 mRNA upregulation, and altered behavior in mice deficient for the close homolog of L1. Mol Cell Biol 2002, 22:7967-7981.
59. Kopan R, Ilagan MX The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 2009, 137:216-233.
60. Hong L, Turner RT, Koelsch G, Shin D, Ghosh AK, Tang J Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3. Biochemistry 2002, 41:10963-10967.
61. Hong L, Koelsch G, Lin X, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science 2000, 290:150-153.
62. Probst G, Xu YZ Small-molecule BACE1 inhibitors: a patent literature review (2006-2011). Expert opinion on therapeutic patents. Expert Opin Ther Pat 2012, 22:511-540.
63. Evin G, Lessene G, Wilkins S BACE inhibitors as potential drugs for the treatment of Alzheimer's disease: focus on bioactivity. Recent Patents CNS Drug Discov 2011, 6:91-106.
64. Atwal JK, Chen Y, Chiu C, et al. A therapeutic antibody targeting BACE1 inhibits amyloid-β production in vivo. Sci Transl Med 2011, 3:84ra43.
65. Yu YJ, Zhang Y, Kenrick M, et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 2011, 3:84ra44.
66. Forman M, Palcza J, Tseng J, et al. The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single- and multiple-dose administration. Alzheimers Dement 2012, 8:704.
67. Forman M, Kleijn H, Dockendorf M, et al. The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid in patients with mild-to-moderate Alzheimer's disease. Alzheimers Dement 2013, 9:139.
68. May PC, Dean RA, Lowe SL, et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci 2011, 31:16507-16516.
69. Martenyi F, Dean RA, Lowe S, et al. BACE inhibitor LY2886721 safety and central and peripheral PK and PD in healthy subjects (HSs). Alzheimers Dement 2012, 8:583-584.
70. Willis B, Martenyi F, Dean R, et al. Central BACE1 inhibition by LY2886721 produces opposing effects on APP processing as reflected by cerebrospinal fluid sAPPalpha and sAPPbeta. Alzheimers Dement 2012, 8:582.
71. May PC, Mergott DJ, Cocke PJ, et al. Preclinical and phase I clinical characterization of LY2886721, a BACE inhibitor in Phase II development Alzheimer's disease. The 11th International Conference On Alzheimer's & Parkinson's Diseases. Florence, Italy; March 6-10, 2013.
72. 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 beta-amyloid levels after single dosing. Alzheimers Dement 2012, 8(suppl):96.
73. Lai R, Albala B, Kaplow JM, et al. Novel BACE1 inhibitor E2609 reduces plasma and CSF amyloid in health subjects after 14 days oral administration. The 11th International Conference On Alzheimer's & Parkinson's Diseases. Florence, Italy; March 6-10, 2013.
74. Bernier F, Sato Y, Matijevic M, et al. Clinical study of E2609, a novel BACE1 inhibitor, demonstrates target engagement and inhibition of BACE1 activity in CSF. Alzheimers Dement 2013, 9:886.
75. Li R, Lindholm K, Yang LB, 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, 101:3632-3637.
76. Yang LB, Lindholm K, Yan R, et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 2003, 9:3-4.
77. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002, 59:1381-1389.
78. Holsinger RMD, McLean CA, Beyreuther K, Masters CL, Evin G Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease. Ann Neurol 2002, 51:783-786.
79. Zhao J, Fu Y, Yasvoina M, et al. Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci 2007, 27:3639-3649.
80. Zhang XM, Cai Y, Xiong K, et al. Beta-secretase-1 elevation in transgenic mouse models of Alzheimer's disease is associated with synaptic/axonal pathology and amyloidogenesis: implications for neuritic plaque development. Eur J Neurosci 2009, 30:2271-2283.
81. Jack CR Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology 2012, 263:344-361.
82. Holtzman DM, Morris JC, Goate AM Alzheimer's disease: the challenge of the second century. Sci Transl Med 2011, 3:77sr1.
83. Musiek ES, Holtzman DM Origins of Alzheimer's disease: reconciling cerebrospinal fluid biomarker and neuropathology data regarding the temporal sequence of amyloid-beta and tau involvement. Curr Opin Neurol 2012, 25:715-720.
84. Tarawneh R, Holtzman DM The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment. Cold Spring Harb Perspect Med 2012, 2:a006148.
85. Salzer JL Axonal regulation of Schwann cell ensheathment and myelination. J Peripher Nerv Syst 2012, 17(suppl 3):14-19.