Dobry amyloid β? Właściwości chemiczne peptydów Aβ4-x wskazują na ich znaczenie biologiczne

Alzheimer’s Disease is a neurodegenerative condition, an irreversible progressive dementia caused by death of neurons in brain structures responsible for memory related processes. Despite many years of research and numerous trials, no therapy succeeded that could stop the development of this disease, which affects tens of millions of patients worldwide. The amyloid cascade prevails among a variety of possible mechanisms of its development proposed in the scientific literature. It proposes that death of neurons, preceded by dysfunction of their synaptic activity is caused by the incremental formation of structures (fibrils, oligomers) composed of Aβ peptides. In its copper variant the processes of aggregation and oxidative stress, causing the inflammation and neuronal damage are related to the formation of reactive Cu(II) complexes with Aβ peptides. Aβ peptides are a family of molecules with similar amino acid sequences, differing mainly by the presence of longer or shorter terminal sequences. Their physiological role of is unclear. Aβ_1-42 and Aβ_1-40 have been mostly studied, but most studies have ignored a very abundant N-terminally truncated species Aβ_4-42. We recognized it, and more gene-rally the Aβ_4-x peptide family as potentially strong Cu(II) ligands, due to the presence at their N-termini of the Phe-Arg-His amino acid sequence, comprising the ATCUN/NTS structural motif. This observation was followed by vigorous research performed in our laboratory. We studied the ability of Aβ_4-x peptides to bind Cu(II) ions, their electrochemical properties and redox reactivity, interactions with proteins which bind copper under physiological conditions, their aggregation properties in the Cu(II) presence and susceptibility to proteolysis. Additionally, we investigated their interaction with a molecule of a therapeutic potential. We demonstrated that Aβ4-x peptides can be primary copper bin-ding agents in extracellular spaces in the brain, able to instantaneously intercept copper from Aβ_1-x peptides studied so far. Cu(II) complexes of Aβ_4-x peptides are highly resistant to oxidation and reduction, release copper ions to other molecules slowly and reluctantly, and do not produce reactive oxygen species. In accordance with these properties we proposed a physiological role for the Aβ_4-42 peptide as a molecule cleansing the synaptic cleft from Cu²⁺ ions and thereby assuring the correct neurotransmission. This function can however be disturbed by an inappropriate pharmacological intervention. The results of studies of the effect of cupric ions on the aggregation and membrane interactions of the Aβ_4-40 peptides suggest that copper can inhibit the Aβ_4-x peptides toxicity, thereby providing an additional support for our concept. Studies of hydrolysis of Aβ peptides and properties of its products revealed a possibility for a significant role of short fragments in the brain copper physiology. Our hypothesis awaits verification by biological studies. The issue of metabolism of the studied complexes is a key issue remaining to be solved.