Abstract
Alzheimer’s disease, the most common form of dementia, is characterized by the aggregation of amyloid beta protein (Aβ). The aggregation and toxicity of Aβ are strongly modulated by metal ions and phospholipidic membranes. In particular, Cu2+ ions play a pivotal role in modulating Aβ aggregation. Although in the last decades several natural or synthetic compounds were evaluated as candidate drugs, to date, no treatments are available for the pathology. Multifunctional compounds able to both inhibit fibrillogenesis, and in particular the formation of oligomeric species, and prevent the formation of the Aβ:Cu2+ complex are of particular interest. Here we tested the anti-aggregating properties of a heptapeptide, Semax, an ACTH-like peptide, which is known to form a stable complex with Cu2+ ions and has been proven to have neuroprotective and nootropic effects. We demonstrated through a combination of spectrofluorometric, calorimetric, and MTT assays that Semax not only is able to prevent the formation of Aβ:Cu2+ complexes but also has anti-aggregating and protective properties especially in the presence of Cu2+. The results suggest that Semax inhibits fiber formation by interfering with the fibrillogenesis of Aβ:Cu2+ complexes.
Highlights
Alzheimer’s disease represents the most common neurodegenerative disease.[1]
We demonstrated through a combination of spectrofluorometric, calorimetric, and MTT assays that Semax is able to prevent the formation of Aβ:Cu2+ complexes and has anti-aggregating and protective properties especially in the presence of Cu2+
We investigate the ability of Semax to interfere with the early phase of Aβ aggregation by incubating the compound with monomeric forms of amyloid-β 1−42 (Aβ1−42) for 48 h at low temperature and under gentle rotation to slow the rate of reaction (Figure 2)
Summary
Alzheimer’s disease represents the most common neurodegenerative disease.[1]. According to data from the World Alzheimer Report, over 46.8 million people were affected by dementia worldwide in 2015, with a prevision of a doubling of this number in the 20 years.[2,3] To date, despite the intense research activity, the etiology of the pathology is not fully understood. The principal hallmark of Alzheimer’s disease is the appearance in the hippocampal region of the brain[4] of proteinaceous deposits inside neuronal cells, called neurofibrillary tangles, mainly constituted by fibrillar aggregates of phosphorylated tau protein,[5] and in the extracellular space, called amyloid plaques, mainly constituted by fibrillar aggregates of amyloid beta protein (Aβ).[6] Amyloid β protein is the final product of the aberrant cleavage of amyloid precursor protein (APP).[7]. It was proposed that an abnormally high concentration of Aβ could result in aggregation into a β-sheet rich structure, the starting point of the fibrillogenesis of Aβ.[8] Aggregation is a complex mechanism that starts with the formation of oligomeric species, suggested to be the more toxic species for cells,[9,10] that undergo conformational reorganization into protofibrils and fibrils. It is widely recognized that metal ions, in particular copper, are involved in the aggregation process of several protein and amyloidogenic peptides.[13−15]
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