Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Abstract

Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β-sheet breaker α/β-hybrid peptide (BSBHp) and the underlying mechanisms against Aβ -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with the peptide Aβ to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca , and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ -induced toxicity by retaining cell viability, suppressing generation of ROS, Ca levels, and effectively protects neuronal apoptosis by suppressing pro-apoptotic protein Bax and up-regulating antiapoptotic protein Bcl-2. These results suggest that α/β-hybrid peptide has neuroprotective effects against Aβ -induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis

“…It is involved in the pathological process of AD and acts as a protective factor. [23] Taken together, the above evidence supported the notion that the hub genes might play critical roles in Mn-induced AD. However, it is still unknown whether these above hub genes can be used as potential targets for disease prevention and therapy.…”

Naphthoquinone–Dopamine Hybrids Inhibit α‐Synuclein Aggregation, Disrupt Preformed Fibrils, and Attenuate Aggregate‐Induced Toxicity

“…To evaluate whether the hybrid molecules can reduce the toxicity of α‐Syn oligomers and fibrils, we employed two complementary assays, one involving large unilamellar vesicles (LUVs) and the other involving cultured neuronal cells. Monitoring the extent of leakage of the carboxyfluorescein dye from LUVs loaded with it is a commonly used proxy for damage to cell membrane and cytotoxicity caused for example, by amyloids [56–59] …”

“…Monitoring the extent of leakage of the carboxyfluorescein dye from LUVs loaded with it is a commonly used proxy for damage to cell membrane and cytotoxicitycaused for example, by amyloids. [56][57][58][59] Prior to the leakagea ssay,L UVs were prepared freshly and their formation was confirmed by TEM ( Figure S18). To perform the leakage assay, a-Syn (10 mm)w as allowed to aggregatef or 10 hi nt he absence of the tested molecules (NQDA, Cl-NQDA and DA), the time at which a-Syn is assumed to form oligomers, as inferred from the ThT results ( Figure2a, black curve).…”

Computational design and evaluation of β‐sheet breaker peptides for destabilizing Alzheimer's amyloid‐β42 protofibrils

“…8,12 A landmark in the history of AD therapeutics is the development of β-sheet breaker (BSB) peptides based on the sequence of Aβ. 13,14 The BSB peptides are an interesting class of peptide based inhibitors as they target the β-sheet structure of Aβ peptide which is directly associated with the neurotoxicity in AD. 13,14 In 1996, Soto and coworkers synthesized an 11 amino acid long peptide inhibitor (iAβ11 and RDLPFFPVRID) of Aβ fibril formation based on Aβ [17][18][19][20][21] sequence.…”

“…13,14 The BSB peptides are an interesting class of peptide based inhibitors as they target the β-sheet structure of Aβ peptide which is directly associated with the neurotoxicity in AD. 13,14 In 1996, Soto and coworkers synthesized an 11 amino acid long peptide inhibitor (iAβ11 and RDLPFFPVRID) of Aβ fibril formation based on Aβ [17][18][19][20][21] sequence. 15 In spite of having similar hydrophobicity to parent sequence, iAβ11 display negligible propensity to adopt β-sheet conformation.…”