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Neurodegenerative diseases are a group of pathologies that mainly affect neurons of the human brain. Particularly, Alzheimer disease (AD) is a neurodegenerative disorder, being manifested by neuronal and synaptic loss. One of the main pathological aspects of AD is aggregation of amyloid-β (Aβ) peptide. However, there are some neuropeptides that play an important role in immunity and neuroprotection. In addition, the presence of metal ions and their abnormal accumulation play a key role in this pathology. The interaction of Aβ peptides with metal ions produces a change in peptide conformation and leads to the occurrence of peptide-metal complexes. However, the molecular mechanism of Aβ neurotoxicity has not thoroughly been elucidated. Therefore, we focused on a particular neuroprotective peptide, called NAP, a small fragment derived from ADNP (activity-dependent neurotrophic protein), which is essential for a proper function of the brain. Here, we report the synthesis of some new structural analogs of both Aβ(9-16) peptide fragment and NAP peptide, which were investigated in the presence of copper and iron ions. Thus, in the native Aβ(9-16) sequence 9GYEVHHQK16, tyrosine (Tyr, Y10) and histidine (His, H13,14) residues were replaced with glycine (Gly). In parallel, serine (Ser, S5) residue was modified with glycine (Gly, G5) or histidine (His, H5) in the sequence of neuroprotective NAP peptide (¹NAPVSIPQ8). All peptides were synthesized by Fmoc/tbutyl solid-phase synthesis (SPPS) and their structure as well as that of metal-peptide complexes was confirmed by MALDI-TOF mass spectrometry. Purification and separation of the peptides were performed by reverse phase high performance liquid chromatography (RP-HPLC). [ABSTRACT FROM AUTHOR]

Alzheimer`s diseases (AD) is the most common age-related dementia, being characterized by accumulation of extracellular amyloid plaques in AD brains. The principal constituent of these plaques are fibrils which are primarily composed of amyloid-β peptides (A), with 39-42 amino acid residues in length, which are the proteolysis products derived from the amyloid precursor peptide (APP). Several factors, such as oxidative stress, inflammation, metal ions or genetic factors are associated with AD. Even if metal ions are involved in many biological and biomedical processes, several studies suggest that copper, zinc, iron, aluminum, etc. are implicated in neurotoxicity of Aβ peptides. Beside the interest in studying the AD biochemical process, there is also a high interest in studying the anti-amyloid peptides, such as the NAP peptide, due to their neuroprotective activities. Here, we report on the synthesis of both amyloid-β peptides and neuroprotective peptides that interact with several metal ions. Both peptides and their complexes with metals have been characterized by mass spectrometry (MS), infrared spectroscopy (FT-IR) and atomic force microscopy (AFM). Therefore, we synthesized by solid phase peptide synthesis procedure, the native Aβ1- 16 (¹DAEFRHDSGYEVHHQK16) peptide, 2 mutated Aβ1-16 peptides, in which His6,13,14 residues were replaced by serine (Aβ(S6,13,14)1-16: ¹DAEFRSDSGYEVSSQK16) and alanine (Aβ(A6,13,14)1-16: 1DAEFRADSGYEVAAQK16) as well as the NAP peptide (1NAPVSIPQ8) and three of its analogs with glycine (NAPG: ¹NAPVGIPQ8), alanine (NAPA: ¹NAPVAIPQ8) and histidine (NAPH: ¹NAPVHIPQ8). Our mass spectrometric data and, especially the MS/MS ones show that all peptides interact with the metal ions studied and suggest that the formation of complex between metal ions and peptides depends on the type of metal used as well as the amino acid residues involved in metal binding. The AFM images indicate that the more hydrophobic AβAla)1-16 forms easier fibrils than the native Aβ peptide in the presence of metal ions, especially aluminum or even as a free peptide. [ABSTRACT FROM AUTHOR]