Biomedicine & Pharmacotherapy (Feb 2023)
Antagonising a novel toxin “T14” in Alzheimer’s disease: Comparison of receptor blocker versus antibody effects in vitro
Abstract
A 14mer peptide, T14, is a possible signaling molecule driving neurodegeneration. Its levels are doubled in the Alzheimer brain, but its effects can be blocked at the target alpha-7 receptor by a cyclised variant, ‘NBP14′, which has beneficial effects, in a transgenic mouse model, on the behavioral and histochemical profile. Since the antagonism of T14 has evident therapeutic potential, we explore here an alternative method of preventing its action by comparing the efficacy of NBP14 with a proprietorial polyclonal antibody against T14, ‘Ab-19′, at inhibiting three distinct effects of the peptide in PC12 cells: calcium influx, cell viability and compensatory acetylcholinesterase (AChE) release. None of these three parameters was affected by either blocking agent when applied alone. However, both NBP14 and the Ab-19 exhibited a dose-dependent profile against the actions of T14 in all three scenarios: the least sensitive effect observed was in the lower dose range, for both the antibody and the receptor blocker, in antagonizing T14-triggered release of AChE: this parameter is interpreted as indirect compensation for the T14-induced compromise of cell viability, triggered by the enhanced influx of calcium through the initial binding of the peptide to an allosteric site on the alpha-7 receptor. As such, it is the most delayed and indirect index of T14 action and thus the least relatively impacted by lowest doses of either NBP14 or Ab-19. In all three scenarios however the effects of T14 are successfully offset by either agent and thus offer two potentially very different therapies against Alzheimer’s disease.
