Semax, a Synthetic Regulatory Peptide, Affects Copper-Induced Abeta Aggregation and Amyloid Formation in Artificial Membrane Models

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.

Harnessing the Therapeutic Potential of Peptides for Synergistic Treatment of Alzheimer’s Disease by Targeting Aβ Aggregation, Metal-Mediated Aβ Aggregation, Cholinesterase, Tau Degradation, and Oxidative Stress

“…Attanasio and co-workers evaluated the antiaggregation and neuroprotective properties of Semax (heptapeptide= Met-Glu-His-Phe-Pro-Gly-Pro) in the presence and absence of Cu 2+ ions and model membranes . Semax is an analog of the endogenous regulatory peptide Met-Glu-His-Phe-Arg-Trp-Gly and is known to exhibit nootropic, neuroprotective, and neurotrophic properties.…”

“…Attanasio and co-workers evaluated the antiaggregation and neuroprotective properties of Semax (heptapeptide= Met-Glu-His-Phe-Pro-Gly-Pro) in the presence and absence of Cu 2+ ions and model membranes. 69 Semax is an analog of the endogenous regulatory peptide Met-Glu-His-Phe-Arg-Trp-Gly and is known to exhibit nootropic, neuroprotective, and neurotrophic properties. The kinetic ThT assay predicted that Semax inhibited Aβ 40 aggregation in a dose-dependent manner and induced a longer lag phase followed by a rapid elongation rate as compared to Aβ 40 alone, suggesting the stabilization of oligomers as the most plausible mechanism.…”

“…Several MTD peptides against AD reported in this review can themselves act as guiding chemotypes for the development of potent therapeutics against AD. 46 tested in cellular model (SH-SY5Y cells) LA-GPE 47 tested in cellular model (SH-SY5Y cells) GS(HQ)H 48 tested in cellular model (SH-SY5Y cells) ZW1 51 tested in transgenic mouse model GGH 52 tested in cellular model (PC12 cells) P6 53 tested in cellular model (PC12 cells) GR 54,55 tested in cellular model (PC12 cells) and rat model GSH-LD 56 tested in cellular model (U937 cell lines) LK7-HH 58 tested in cellular model (PC12 cells) Car-LK7 59 tested in cellular model (SH-SY5Y cells) RK10 61 tested in cellular model (SH-SY5Y cells) rk10 62 tested in cellular model (SH-SY5Y cells) Glupep 66 tested in cellular model (PC12 cells) MPLT3, MPGLT 67 tested in cellular model (SH-SY5Y cells) PA 19 fCP 68 tested in cellular model (N2a cells) Semax 69 tested in cellular model (SH-SY5Y cells) DS2 70 tested in cellular model (SH-SY5Y cells) WRR, ERW 71 tested in cellular model (SH-SY5Y cells) TH006 74 tested in rat model AI 75 tested in cellular model (PC12 cells) LE6 76 tested in cellular model (PC12 cells) SLKP 77 tested in cellular model (PC12 cells) NVR 78 tested in cellular model (PC12 cells) W3 79 tested in brine shrimp RA-1 80 tested in cellular model (PC12 cells) LME-tet 85 tested in cellular model (N2a cells)…”

The role of sperm-specific glyceraldehyde-3-phosphate dehydrogenase in the development of pathologies—from asthenozoospermia to carcinogenesis

“…It is widely recognized that copper ions not only interact and form complexes with Aβ but are also involved in the aggregation of amyloidogenic peptides ( Thakur et al, 2011 ; Attanasio et al, 2013b ). Many peptide inhibitors of Aβ aggregation ( Attanasio et al, 2013a ; Wang et al, 2014 ; Barrera Guisasola et al, 2015 ; Greco et al, 2020 ) and copper chelators ( Tabbì et al, 2015 ; Magrì et al, 2016 ; Sciacca et al, 2022 ) have been proposed for the treatment of AD ( Ryan et al, 2018 ). Moreover, a significant inhibitory effect on GAPDH activity was obtained with copper that suggests the involvement of mainly catalytic cysteine and neighboring histidine residues in the binding of this metal ( Krotkiewska and Banaś, 1992 ).…”

Aβ8-20 Fragment as an Anti-Fibrillogenic and Neuroprotective Agent: Advancing toward Efficient Alzheimer’s Disease Treatment

“…Dementia is a significant contributor to loss of independence, disability, and care home placement and represents one of the costliest long-term pathologies to society, with 85% of costs related to family or social care . 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 next 20 years. − To date, despite the high interest of the scientific community, the etiopathogenesis of the disease is not fully understood, and no drugs are still available for the treatment despite the large number of clinical trials and the intense research activity on synthetic and/or natural compounds. − …”