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Review
. 2016 Jul 20;7(7):845-56.
doi: 10.1021/acschemneuro.6b00154. Epub 2016 Jul 5.

Modulation of Amyloid β-Protein (Aβ) Assembly by Homologous C-Terminal Fragments as a Strategy for Inhibiting Aβ Toxicity

Huiyuan Li  1 , Farid Rahimi  2 , Gal Bitan  3
Affiliations
Review

Modulation of Amyloid β-Protein (Aβ) Assembly by Homologous C-Terminal Fragments as a Strategy for Inhibiting Aβ Toxicity

Huiyuan Li et al. ACS Chem Neurosci. .

Abstract

Self-assembly of amyloid β-protein (Aβ) into neurotoxic oligomers and fibrillar aggregates is a key process thought to be the proximal event leading to development of Alzheimer's disease (AD). Therefore, numerous attempts have been made to develop reagents that disrupt this process and prevent the formation of the toxic oligomers and aggregates. An attractive strategy for developing such reagents is to use peptides derived from Aβ based on the assumption that such peptides would bind to full-length Aβ, interfere with binding of additional full-length molecules, and thereby prevent formation of the toxic species. Guided by this rationale, most of the studies in the last two decades have focused on preventing formation of the core cross-β structure of Aβ amyloid fibrils using β-sheet-breaker peptides derived from the central hydrophobic cluster of Aβ. Though this approach is effective in inhibiting fibril formation, it is generally inefficient in preventing Aβ oligomerization. An alternative approach is to use peptides derived from the C-terminus of Aβ, which mediates both oligomerization and fibrillogenesis. This approach has been explored by several groups, including our own, and led to the discovery of several lead peptides with moderate to high inhibitory activity. Interestingly, the mechanisms of these inhibitory effects have been found to be diverse, and only in a small percentage of cases involved interference with β-sheet formation. Here, we review the strategy of using C-terminal fragments of Aβ as modulators of Aβ assembly and discuss the relevant challenges, therapeutic potential, and mechanisms of action of such fragments.

Keywords: Alzheimer’s disease; aggregation; amyloid; oligomerization; peptide; toxicity.

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Figures

Figure 1
Figure 1
Amino acid sequence of Aβ42. Color code: Brown = nonpolar, purple = polar, blue = negatively charged, and magenta = positively charged. The CHC and C-terminal regions are underlined.
Figure 2
Figure 2
Particle growth rate. (A) Time course of average RH was calculated from whole particle size distributions in solutions of Aβ(29–42), Aβ(30–42), Aβ(31–42), Aβ(33–42), or Aβ(30–40) at indicated concentrations. Each data point represents mean ± SEM calculated from the average RH of eight consecutive DLS measurements during 45–60 min. Aggregation of Aβ(29–42) and Aβ(30–42) was followed until the upper limit of detection was reached. (B) Average aggregation rates of Aβ(29–42), Aβ(30–42), Aβ(31–42), Aβ(33–42), and Aβ(30–40). The data represent mean ± SEM of three independent experiments. Reproduced from ref 3. Copyright 2010 American Chemical Society.
Figure 3
Figure 3
Sequence alignment of Aβ(30–40) and Aβ(32–42).
Figure 4
Figure 4
Time–dependent conformational changes during CTF aggregation. (A) Representative CD spectra of 62 μM Aβ(31–42) recorded in 24–h time intervals. (B) Representative time course of β-sheet formation shown for Aβ(29–42), Aβ(30–42), Aβ(31–42), Aβ(33–42), Aβ(34–42), and Aβ(30–40) at the indicated concentrations. Reproduced from ref 3. Copyright 2010 American Chemical Society.
Figure 5
Figure 5
Structures of the N–Methylated Peptides 1–4. Reproduced from ref 1. Copyright 2009 American Chemical Society.
Figure 6
Figure 6
Inhibition of Aβ42 hexamer formation. Aβ42 was cross-linked in the absence or presence of increasing concentrations of each CTF and analyzed by SDS–PAGE and silver staining. Aβ(21–30) was used as a negative control. The amount of Aβ42 hexamer was determined densitometrically and normalized to the protein content in the entire lane. IC50 values are the CTF concentrations required for 50% inhibition of Aβ42 hexamer formation. Reproduced from ref 4. Copyright 2010 American Chemical Society.
Figure 7
Figure 7
CTF effects on Aβ42 particle size distribution. Representative distribution of Aβ42 in the absence or presence of CTFs immediately after preparation (left), on the next day (center), and after 4–7 days (right). White bars represent data from P1 particles. Gray bars represent data for P2 or larger particles (in the case of Aβ42 alone). The numbers in the upper left corner correspond to the total scattering intensity measured in each sample. Reproduced from ref 4. Copyright 2010 American Chemical Society.
Figure 8
Figure 8
Schematic representation of a putative mechanism by which CTFs affect Aβ42 assembly. Monomer (M) assembly into P1 particles is a faster process in the absence (top path) than in the presence (bottom path) of CTFs. CTFs may accelerate the conversion of P1 into P2 oligomers, but effective inhibitors of Aβ42–induced toxicity induce smaller acceleration than ineffective ones, shifting the population toward P1. All CTFs slow the maturation of P2 assemblies into fibrils (F). Reproduced from ref 4. Copyright 2010 American Chemical Society.
Figure 9
Figure 9
Schematic diagram of our group's two–step N–methylation strategy for Aβ(31–42) SAR studies. Reproduced from ref 2. Copyright 2012 Wiley–VCH Verlag GmbH & Co. KGaA.
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