Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

Abstract

Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrillar aggregates of Aβ exhibit different levels of neuronal toxicity. Moreover, aggregation of Aβ in the presence of redox-active metal ions like Cu(2+) is responsible for the additional trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of Aβ aggregation. It was shown by employing various biophysical studies that P6 interact with Aβ and prevent the formation of toxic Aβ forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu(2+) from the Aβ-Cu(2+) complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by Aβ oligomers and efficiently prevented DNA damage caused by the Aβ-Cu(2+) complex. PC12 cells were rescued from multifaceted Aβ toxicity when treated with P6, and the amount of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted Aβ toxicity in AD.

The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization

“…In the past, several strategies have been developed to reduce or prevent Aβ production and to destabilize Aβ aggregates, including immunotherapeutic vaccines [15,16], antibodies [17,18], peptides [19,20], nanoparticles [21][22][23] and compounds targeting Aβ secretases [24,25] and Aβ aggregation [26][27][28][29][30][31]. However, some of these approaches have shown serious side effects [32,33] and poor permeability through the blood-brain barrier (BBB) [34].…”

Aβ plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies

“…The solution was incubated at 37 °C for 1 h, after which the sample was incubated for 24 h at 4°C. The obtained sample was centrifuged, and the supernatant with oligomers was used for further experiments (Walsh et al, 1997; Stine et al, 2011; Rajasekhar et al, 2016a, 2016b). …”

“…While PET imaging is an important tool to image protein aggregates, it is expensive and hazardous to human health due to the use of radio-labeled nuclei (Zhu et al, 2014). Consequently, much attention has been focused on the development of NIR fluorescence probes owing to their easy synthesis, non-invasive nature, low cost, long shelf-life, minimal interference from auto-fluorescence and greater penetration depth to extract information from deep inside the specimen; these attributes make them ideal candidates as diagnostic and imaging agents for toxic Aβ aggregates (Staderini et al, 2015; Narayanaswamy et al, 2016, 2015; Rajasekhar et al, 2016a, 2016b; Li et al, 2016; Ren et al, 2016; Kim et al, 2015; Cui et al, 2014; Hintersteiner et al, 2005; Cao et al, 2012; Lv et al, 2016; Hatai et al, 2017; Gao et al, 2017; Yin et al, 2015; Han et al, 2016; Yu et al, 2015; Xie et al, 2015). Herein, we report a low molecular weight ( > 600 Da) coumarin-quinoline ( CQ ) conjugate-based NIR fluorescence probe (Zhu et al, 2013) for selective detection of Aβ fibrillar aggregates, and its preferential staining of Aβ plaques in the human brain tissue over NFTs (Fig.…”

Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

“…These facts and reports have underscored the importance of clearing or reducing the Aβ burden from the brain as a primary target to develop therapeutic agents for the treatment of AD (17)(18)(19). The amyloid toxicity emphasizes the need for a novel drug design strategy to ameliorate Aβ burden-associated plasma membrane toxicity, cognitive decline and memory (STM and LTP) impairment under progressive AD pathogenesis (20)(21)(22). We designed and synthesized a set of novel small molecules (TGR60-…”