Antagonism of a key peptide 'T14' driving neurodegeneration: Evaluation of a next generation therapeutic

Abstract

T14, a 14mer peptide derived from the C-terminus of acetylcholinesterase (AChE) is a signalling molecule that could drive neurodegeneration via the alpha 7 nicotinic acetylcholine receptor. Its levels increase as Alzheimer’s pathology progresses; however, a cyclic variant of the compound, NBP14, can block the effects of the endogenous linear counterpart in-vitro, ex vivo, and in vivo. Here, we explore the antagonistic potential of two 6mer peptides, NBP6A and NBP6B. These are smaller linear versions of NBP14, designed to be more effective by modifying the amino acid residues to enhance receptor blockade alongside other relevant solubility parameters. The peptides were tested in-vitro in PC12 cells on three parameters, calcium influx, cell viability, and AChE release, and ex vivo using voltage sensitive dye imaging (VSDI) in rat brain slices. Neither NBP6A nor NBP6B applied alone had any effect. In PC12 cells, NBP6B was identified as the more potent molecule since it demonstrated more effective blockade of T14 action on calcium influx, cell viability, and AChE release. NBP6B was then further evaluated using VSDI, where it proved twice as potent as NBP14 in blocking the action of T14. The improved effect of NBP6B in blocking the actions of T14, combined with its smaller size suggests that this variant could have even greater therapeutic potential than its original cyclic compound, for treating neurodegenerative disorders.