All tags Neuroscience Beta amyloid in Alzheimer's disease: APP processing

Beta amyloid in Alzheimer's disease: APP processing

Alzheimer's disease is characterized by the presence of neurotoxic beta amyloid (Aß) deposits in the brain. This article describes the generation 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 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

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

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.


BACE inhibitors

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.

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), about 14-fold selectivity over BACE-2 (Ki = 372 nM)14.

ab223887

Lanabecestat (AZD3293)


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.

ab223888

Loganin


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

ab143653

LY2886721


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

ab223886

Nilvadipine


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

ab141311

Verubecestat (MK-8931)


Selective, potent 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

See all beta amyloid products

β-secretase

Anti-BACE1 antibody

β-secretase activity assay kit

See all β-secretase products


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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