Therapeutic antagonism of a key toxin driving Alzheimer’s disease: Comparison of a peptide variant and small molecule

Abstract

Among emerging therapeutic targets for Alzheimer’s disease (AD), the α7 nicotinic acetylcholine receptor (α7-nAChR) has received much attention and now merits still more focus due to its role as the exclusive binding site for the toxic 14mer peptide T14. T14 is elevated in presymptomatic AD and initiates a pathological cascade involving calcium influx, mTORC1 activation, impaired autophagy, and β-amyloid accumulation. To interrupt this sequence, the cyclated variant of T14, NBP14, was developed, with consequent cognitive benefits in a preclinical mouse model. However, the high molecular weight of NBP14 posed potential limitations for therapeutic translation, prompting the design of NBP6B, a shorter, linear 6-mer variant with improved efficacy and bioavailability. This study aimed to evaluate the efficacy of NBP6B in antagonising T14-induced toxicity in comparison with two novel small molecules, which due to their lower molecular weight could have greater therapeutic potential. Using PC12 cells, T14 activity was assessed through calcium influx and cell viability assays, alongside therapeutic rescue by the drug candidates. To evaluate receptor specificity, α7-nAChR overexpression was employed to determine whether the small molecules acted via α7-dependent or independent pathways. While the small molecules offered favourable drug-like properties and potential for improved blood–brain barrier (BBB) permeability, NBP6B exhibited greater potency and selectivity, with effective antagonism in the nanomolar range, compared to the micromolar concentrations required for the small molecules. These findings thus support NBP6B as a promising and selective α7-targeted therapeutic for early-stage intervention in AD.