We are beginning to better understand how 'amyloid-β' protein plaques form, which are implicated in degenerative brain diseases including Alzheimer's and Parkinson's diseases. Recent progress made by researchers in Germany may eventually suggest new options for disease prevention or treatment.
The team, at Martin Luther University of Halle Wittenberg, report their findings in the open access journal Bioorganic Chemistry.
Fibrils and plaques
Amyloid-β molecules are small proteins known as peptides, which combine to form aggregates called fibrils, which can then form larger 'plaques'.
Some amyloids have functions in normal health, but damaging amyloid plaques accumulate in the space outside of and between brain cells in degenerative brain diseases, especially Alzheimer's. Some recent evidence suggests the amyloid plaques can also occur inside cells.
Peptides, like all proteins, are composed of amino acid molecules bonded into longer chains. The sequence in which the amino acids are linked determines how peptides and proteins fold into complex structures and interact.
A crucial hairpin turn
The researchers set out to explore the significance of specific amino acids on the folding and interactions of amyloid-β peptides. They achieved this by generating synthetic peptide sequences and incorporating these into the natural peptides to investigate the effect of making specific changes in the amino acid sequence. This included adding amino acids not normally found in peptides, but mimicking the native 'beta-turn' region of the amyloid-β-molecule.
They focused attention on this hairpin turn shaped region of two of the natural peptides known as Aβ40 and Aβ16-35. They identified some amino acid replacements that activated the aggregation of the peptides, but others that inhibited it. This confirms that the structure of the hairpin turn plays an important role in controlling the aggregation process. Learning how to inhibit damaging peptide aggregation might offer crucial insights into preventing the formation of amyloid plaques, or even disrupting existing plaques.
In the most significant finding in terms of clinical potential, mixing specific synthetic peptides with the natural versions inhibited fibrillation, which is considered an important step for plaque formation. These preliminary results were obtained in simple solutions of the peptides, rather than in living cells or animals, but they suggest a promising avenue for future research.
The team also performed toxicity tests in mouse nerve cells as a first step towards exploring the clinical potential of synthetic peptides. These tests revealed "only minor toxicity" of the peptides able to inhibit fibrillation.
The most immediate significance of this work will be to improve understanding of the molecular features that promote amyloid aggregation. But the researchers also note the "large potential" for developing small peptide-based inhibitors of amyloid formation.
The existing options for treating Alzheimer's and related degenerative diseases are very limited, so any potential avenues for improvements are generating keen interest. This current research adds to a growing body of work exploring the clinical potential of modified peptides. The insights gained might also reveal options for using small molecule drugs to interfere with plaque formation, rather than using peptides directly.
Deike, S., et al. (2020) β-Turn mimetic synthetic peptides as amyloid-β aggregation inhibitors. Bioorganic Chemistry. doi.org/10.1016/j.bioorg.2020.104012.