Letter to the Editor

Tackling the Amyloid Beta-Sheet Peptide with Autochthonous Epitopes: Beta-Sheet Breaker Peptides

Izzettin Hatip-Al-Khatib* and Funda Bölükbaşı Hatip
Department of Medical Pharmacology, Pamukkale University, Turkey

*Corresponding author: Izzettin Hatip-Al-Khatib, Department of Medical Pharmacology, Pamukkale University, Denizli, Turkey

Published: 25 Sep, 2018
Cite this article as: Hatip-Al-Khatib I, Hatip FB. Tackling the Amyloid Beta-Sheet Peptide with Autochthonous Epitopes: Beta-Sheet Breaker Peptides. Ann Pharmacol Pharm. 2018; 3(5): 1161.

Letter to the Editor

The extracellular β-amyloid deposits in brain parenchyma in the form of plaques are one of the pathological hallmarks of Alzheimer's disease (AD). In order the Aβ in the plaques to become pathogenic, it should be oligomerized and fibrillized. It has been reported that the central hydrophobic cluster of amino acids 17-21 (LVFFA) is important in both amyloid fibril formation and stability. The residues 16-27 and 30-36 of Aβ42 also display β-structures [1], whereas other hydrophobic domains containing amino acids 16-20 (KLVFF) of Aβ have also been reported to be fundamental for Aβ protein–protein interaction [2]. The efficacy of the depends on their binding affinity: the stronger the ligand binding, the slower the oligomerization process [3].
The therapeutic agents used in treatment of AD neither target Aβ, nor cure the pathological changes that it induces. Accordingly, a therapeutic strategy that could either prevent formation and/or facilitate dissolution of the misfolded Aβ aggregates, decrease its neurotoxicity and memory impairing activity could be of great value in treatment of AD. Aβ fragment(s) containing the central core of the main Aβ, with a less propensity to adopt β sheet conformation, but able to bind to the full length Aβ and prevent its assembly into amyloid fibrils are known as beta sheet breaker peptide (βSBP). The BSBP 17-21 (LVFFA) [4], LPFFD [5,6], RVVIA [7], 16-20 [4] interfere with fibril formation and increase neuronal survival. Moreover, eight-residue Aβ-derived fragments Aβ1-8, Aβ9-16 and Aβ1-16 had been reported to inhibit caspases pathways activation and protect against Aβ40-induced apoptosis of neuronal cells [8].
We [9] have previously found that the eight-residue βSBPs (especially the βSBP 15–22), without any substitution of the original amino acids, could decrease Aβ40 burden, Aβ-induced cellular changes in amygdala and hippocampus, and Aβ-induced memory impairment. The octapeptide βSBPs we used also improved the Aβ-impaired vascular responses to vasodilators [10]. βSBPs increase Aβ removal by at least two possible mechanisms [11]. The first is that βSBPs may act as an immune complex that activates microglia to a greater extent than Aβ fibrils alone. This scenario may then result in enhanced phagocytosis and subsequent removal of Aβ. However, we do not think that all βSBPs follow this way because in an in vitro study we have found that βSBPs 15- 22 decreased, the βSBP 16-23 did not change, whereas only the βSBP 17-24 increased microglial activity (our unpublished data). The second mechanism by which βSBPs produce their effects is that βSBPs can bind to the central hydrophobic cluster, via hydrogen bridges in a manner rendering the βSBP sitting in the central hydrophobic region of Aβ on the plane of amyloid dimmer [6], and thereby destabilizing the interaction between Aβ monomers and/or oligomers that is necessary for fibril stability. Aβ develops resistance to protease degradation when polymerized into fibrils in vivo [11] and in vitro [12]. The subsequent loss of fibril integrity may then lead to exposure of cleavage sites facilitating proteolytic processing and removal of Aβ. βSBPs could also induce their effects via increasing digestion of the Aβ40 by protease K, because we have found that βSBPs 16-23 and 17-24 increased Aβ40 digestion by protease K at temperatures 35ºC to 42ºC, and βSBPs 15-22 increased Aβ40 digestion only at high temperatures, 41ºC to 42ºC [13].
Further extensive researches are needed to disclose the efficacy of the βSBPs as one of the candidates for prevention of amyloid aggregation, and therapy of AD.


  1. Yang M, Teplow DB. Amyloid β-protein monomer folding: free energy surfaces reveal alloform-specific differences. J Mol Biol. 2008;384(2):450-64.
  2. Tjernberg LO, Naslund J, Lindqvist F, Johansson J, Karlstrom AR, Thyberg J, et al. Arrest of beta-amyloid fibril formation by a pentapeptide ligand. J Biol Chem. 1996;271(15):8545-8.
  3. Viet MH, Ngo ST, Lam NS, Li MS. Inhibition of Aggregation of Amyloid Peptides by Beta-Sheet Breaker Peptides and Their Binding Affinity. J Phys Chem B. 2011;115(22):7433-46.
  4. Rocha S, Cardoso I, Börner H, Pereira MC, Saraiva MJ, Coelho M. Design and biological activity of β-sheet breaker peptide conjugates. Biochem Biophys Res Commun. 2009;380(2):397-401.
  5. Permanne B, Adessi C, Saborio GP, Fraga S, Frossard M-J, Van Dorpe J, et al. Reduction of amyloid load and cerebral damage in a transgenic mouse model of Alzheimer's disease by treatment with a β-sheet breaker peptide. FASEB J. 2002;16(8):860-2.
  6. Murvai U, Soós K, Penke B, Kellermayer MS. Effect of the beta-sheetbreaker peptide LPFFD on oriented network of amyloid β25-35 fibrils. J Mol Recognit. 2011;24(3):453-60.
  7. Hetenyi C, Szabo Z, Klement T, Datki Z, Kortvelyesi T, Zarandi M, et al. Pentapeptide amides interfere with the aggregation of beta-amyloid peptide of Alzheimer’s disease. Biochem Biophys Res Commun. 2002;292(4):931-6.
  8. Awasthi A, Matsunaga Y, Yamada T. Amyloid-beta causes apoptosis of neuronal cells via caspase cascade, which can be prevented by amyloidbeta- derived short peptides. Exp Neurol. 2005;196(2):282-9.
  9. Hatip FF, Hatip-Al-Khatib I, Matsunaga Y, Suenaga M, Sen N. Effects of 8-Residue Beta Sheet Breaker Peptides on Aged Aβ40–Induced Memory Impairment and Aβ40 Expression in Rat Brain and Serum Following Intraamygdaloid Injection. Curr Alzheimer Res. 2010;7(7):602-14.
  10. Bölükbaşı Hatip FF, Hatip-Al-Khatib I. Effects of β-sheet breaker peptides on altered responses of thoracic aorta in rats' Alzheimer's disease model induced by intraamygdaloid Aβ40. Life Sciences. 2013;92(3):228-36.
  11. Sigurdsson EM, Permanne B, Soto C, Wisniewski T, Frangione B. In vivo reversal of amyloid β-lesions in rat brain. J Neuropathol Exp Neurol. 2000;59(1):11-7.
  12. Nordstedt C, Naslund J, Tjernberg LO, Karlstrom AR, Thyberg J, Terenius L. The Alzheimer Aβ peptide develops protease resistance in association with its polymerization into fibrils. J Biol Chem. 1994;269(49):30773-6.
  13. Bölükbaşı Hatip FF, Suenaga M, Yamada T, Matsunaga Y. Reversal of temperature-induced conformational changes in the amyloidbeta peptide, Abeta40, by the beta-sheet breaker peptides 16-23 and 17-24. Br J Pharmacol. 2009;158(4):1165-72.