Analysis of Neurotoxic Beta Amyloid Peptides in Alzheimer's Disease

Alzheimer's disease is characterized by the presence of neurotoxic beta amyloid (Aß) deposits in the brain. This article briefly explains the production of Aß from amyloid precursor protein (APP).

Aβ peptides are produced by the proteolytic cleavage of the transmembrane protein amyloid precursor protein (APP) by enzyme complexes a, β and γ-secretases.

APP cleavage occurs through two distinct pathways – the amyloidogenic pathway generates neurotoxic Aβ peptides and the non-amyloidogenic pathway provides beneficial neurotrophic effects, as shown in figure 1. Formed through the amyloidogenic pathway, the Aβ peptides misfold and aggregate to create deposits that play a role in the pathology of Alzheimer’s disease.

                 The non-amyloidogenic and amyloidogenic pathways of APP processing.

Figure 1. The non-amyloidogenic and amyloidogenic pathways of APP processing.

The non-amyloidogenic pathway

In the non-amyloidogenic pathway, APP is cleaved by α-secretase to produce two fragments – an N-terminal ectodomain (sAPPα) that is discharged into the extracellular medium and an 83-amino acid C-terminal fragment (C83) that continues to remain in the membrane.

Three enzymes ADAM9, ADAM10 and ADAM171 have been detected with α-secretase activity. Of note, the α-secretase promotes the cleavage of APP within the Aβ domain which thus prevents the production of Aβ peptides.

Importantly, the γ-secretase can later cleave the C83 membrane fragment to generate a C terminal fragment (CTF) and a short fragment known as P3 peptide. It is believed that this P3 peptide is pathologically irrelevant2.

The amyloidogenic pathway

The amyloidogenic pathway promotes the generation of neurotoxic Aβ peptides. The first proteolysis step is mediated by β-secretase (BACE1), discharging a large N-terminal ectodomain (sAPPβ) into the extracellular medium. The membrane contains a 99-amino acid C terminal fragment (C99)3–5.

The C99 N-terminus, which was newly exposed, matches with the first amino acid of Aβ. The Aβ peptide is released through consecutive cleavage of the C99 N-terminal fragment by γ-secretase (between residues 38 and 43). γ-secretase is a complex of enzymes that consist of nicastrin, presenilin 1 or 2 (PS1 and PS2), presenilin enhancer 2 (PEN2), and anterior pharynx defective (APH-1)6–10.

A small percentage of Aβ peptides contain 42 residues (Aβ 1–42), while most of them contain 40 residues in length (Aβ 1–40). However, Aβ 1–42 is believed to be the more neurotoxic form of Aβ peptides because the two additional amino acids have a greater tendency to misfold and aggregate11. Alzheimer’s disease is linked to elevated plasma levels of Aβ 1–4212.

BACE inhibitors

Slowing down the production of Aβ peptides to target its accumulation is gaining rapid importance in the effort to slowdown the progression of Alzheimer’s disease. Access to several β-secretase inhibitors has made it possible to block the APP cleavage. The following table lists of some of the commonly used inhibitors that target Aβ production and β-secretase.

Small molecule

Activity

AbID

β-Secretase Inhibitor II
(Z-VLL-CHO)

Peptidyl β-secretase inhibitor (reversible). Corresponds to the VNL-DA cleavage site on APP13.

ab146640

AZD3839

Potent and selective BACE-1 inhibitor (Ki = 26.1 nM), around 14-fold selectivity over BACE-2 (Ki = 372 nM)14.

ab223887

Lanabecestat (AZD3293)

Highly potent BACE-1 inhibitor with 80 pM (SH-SY5Y cells over-expressing AβPP)15, 310 pM (primary neuron cultures from guinea pigs), and IC50 = 610 pM (primary neuron cultures from mice).

ab223888

Loganin

Selective β-secretase inhibitor. Exhibits neuroprotective effects against Aβ(25-35)-induced cell death16.

ab143653

LY2886721

Selective and potent BACE-1 inhibitor (IC50 = 20.3 nM for recombinant hBACE-1)17.

ab223886

Nilvadipine

Potent Ca2+ channel blocker that promotes Aβ clearance from brain as well as reduced tau hyperphosphorylation18.

ab141311

Verubecestat (MK-8931)

Potent and selective β-sectetase 1 inhibitor (IC50 = 13 nM)19.

ab223883

Recommended Tools to Study Aβ in Alzheimer's Disease

Target

Tools

Beta amyloid

  • Beta amyloid peptide (1–42, human)
  • Near-infrared fluorescent Aβ probes
  • Conformation-specific amyloid beta antibodies

β-secretase

  • Anti-BACE1 antibody
  • β-secretase activity assay kit

References:

  1. Allinson TM, Parkin ET, Turner AJ, Hooper NM (2003). ADAMs family members as amyloid precursor protein α‐secretases. J Neurosci Res, 74, 342–352.
  2. Haass C, Kaether C, Thinakaran G, Sisodia S (2012). Trafficking and Proteolytic Processing of APP. Cold Spring Harb Perspect Med 2, a006270.
  3. Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS et al. (1999). Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol Cell Neurosci 14, 419–427.
  4. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M  et al. (1999). Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature 402, 537–540.
  5. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB et al. (1999). β-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741.
  6. Francis R, McGrath G, Zhang J, Ruddy D A, Sym M, Apfeld J et al. (2002). aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev Cell 3, 85–97.
  7. Levitan D, Lee J, Song L, Manning R, Wong G, Parker E, Zhang L (2001). PS1 N-and C-terminal fragments form a complex that functions in APP processing and Notch signaling. PNAS 98, 12186–12190.
  8. Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A et al. (2002). PEN-2 is an integral component of the γ-secretase complex required for coordinated expression of presenilin and nicastrin. J Biol Chem 277, 39062–39065.
  9. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999). Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature 398, 513–517.
  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.

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Last updated: Apr 1, 2019 at 6:07 AM

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