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Aβ peptides are produced by the proteolytic cleavage of the transmembrane protein amyloid precursor protein (APP) by enzyme complexes α, β and γ-secretases.
APP cleavage occurs via two distinct pathways (Figure 1). The non-amyloidogenic pathway provides beneficial neurotrophic effects and the amyloidogenic pathway produces neurotoxic Aβ peptides. The Aβ peptides formed via the amyloidogenic pathway can misfold and aggregate to form deposits that contribute to Alzheimer’s disease pathology.
Figure 1. The non-amyloidogenic and amyloidogenic pathways of APP processing
The non-amyloidogenic pathway involves cleavage of APP by α-secretase to generate two fragments; an 83 amino acid C-terminal fragment (C83) that remains in the membrane and an N-terminal ectodomain (sAPPα) that is released into the extracellular medium.
Three enzymes have been identified with α-secretase activity: ADAM9, ADAM10 and ADAM171. Importantly, cleavage of APP by α-secretase occurs within the Aβ domain and consequently prohibits Aβ peptide production.
Of note, the C83 membrane fragment can be subsequently cleaved by γ-secretase to produce a short fragment called P3 peptide and a C terminal fragment (CTF). To date, the P3 peptide is believed to be pathologically irrelevant2.
The amyloidogenic pathway leads to neurotoxic Aβ generation. β-secretase (BACE1) mediates the first proteolysis step, which releases a large N-terminal ectodomain (sAPPβ) into the extracellular medium. A 99-amino acid C terminal fragment (C99) remains in the membrane3–5.
The newly exposed C99 N-terminus corresponds to the first amino acid of Aβ. Successive cleavage of this fragment by γ-secretase (between residues 38 and 43) releases the Aβ peptide. γ-secretase is a complex of enzymes consisting of presenilin 1 or 2 (PS1 and PS2), nicastrin, anterior pharynx defective (APH-1) and presenilin enhancer 2 (PEN2)6–10.
Most of the Aβ peptides are 40 residues in length (Aβ 1–40), with a small percentage containing 42 residues (Aβ 1–42). Aβ 1–42 is considered the more neurotoxic form because the extra two amino acids provide a greater tendency to misfold and subsequently aggregate11. Elevated plasma levels of Aβ 1–42 have been correlated with Alzheimer’s disease12.
Targeting Aβ accumulation by slowing its production is gaining importance in the goal to slowdown the progression of Alzheimer’s disease. Blocking APP cleavage is made possible due to access to a number of β-secretase inhibitors. The table below lists of some of the commonly used inhibitors targeting β-secretase and Aβ production.
β-Secretase Inhibitor II
Peptidyl β-secretase inhibitor (reversible). Corresponds to the VNL-DA cleavage site on APP13.
Potent and selective BACE-1 inhibitor (Ki = 26.1 nM), about 14-fold selectivity over BACE-2 (Ki = 372 nM)14.
Highly potent BACE-1 inhibitor with IC50 = 610 pM (primary neuron cultures from mice), 310 pM (primary neuron cultures from guinea pigs), and 80 pM (SH-SY5Y cells over-expressing AβPP)15.
Selective β-secretase inhibitor. Shows neuroprotective effects against Aβ(25-35)-induced cell death16.
Potent and selective BACE-1 inhibitor (IC50 = 20.3 nM for recombinant hBACE-1)17.
Potent Ca2+ channel blocker that promotes Aβ clearance from brain and reduced tau hyperphosphorylation18.
Selective, potent β-sectetase 1 inhibitor (IC50 = 13 nM)19.
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10. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, et al. (2000). Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature, 407, 48–54.
11. Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S et al. (2010). Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils. Nat Struct Mol Biol 17, 561–567.
12. Mayeux R, Tang M-X, Jacobs DM, Manly J, Bell K, Merchant C, Small SA, Stern Y, Wisniewski HM, Mehta PD (1999). Plasma amyloid β-peptide 1–42 and incipient Alzheimer’s disease. Ann Neurol 46, 412–416.
13. Coppola JM, Hamilton CA, Bhojani MS, Larsen MJ, Ross BD, Rehemtulla A (2007) Identification of inhibitors using a cell-based assay for monitoring Golgi-resident protease activity. Anal Biochem 364, 19-29.
14. Jeppsson F, Eketjäll S, Janson J, et al. (2012) Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. J Biol Chem 287, 41245-41257.
15. Eketjäll S, Janson J, Kaspersson K, et al. (2016) AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. J Alzheimers Dis 50, 1109-1123.
16. Kim H, Youn K, Ahn M-R, et al. (2015) Neuroprotective effect of loganin against Aβ25-35-induced injury via the NF-κB-dependent signaling pathway in PC12 cells. Food Funct 6, 1108-1116.
17. May PC, Willis BA, Lowe SL, et al. (2015) The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central A Pharmacodynamic Responses in Mice, Dogs, and Humans. J Neurosci 35, 1199-1210.
18. Paris D, Ait-Ghezala G, Bachmeier C, et al. (2014) The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J Biol Chem 289, 33927-33944.
19. Yan R. (2016) Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl Neurodegener 5, 13.