Site-selective blocking of a bioactive peptide driving neurodegeneration in the rat brain by its cyclised analogue

The substantia nigra (SN) is a primary site of vulnerability in neurodegenerative disorders, where a bioactive peptide 'T14' has been implicated in driving neuronal dysfunction, upstream of the more widely recognised marker, amyloid. T14 acts exclusively at α7 nicotinic acetylcholine receptors (α7 nAChRs / α7 receptors) where its cyclised variant NBP14 has previously been shown to block T14-induced effects in vitro, ex vivo, and in vivo. Here, using an ex vivo slice preparation, we investigated whether NBP14 alters levels of endogenous T14 and α7 receptor content across defined anterior-posterior levels of the rat SN, a region rich in α7 receptors. This was then benchmarked against effects on the striatum (ST), a region with variable α7 receptor density. NBP14 produced a significant but highly site-specific modulation of T14 in the SN, with certain coronal sections showing T14 levels reduced by over threefold. By contrast, no consistent treatment effect was detected in the ST. Total α7 receptor content remained unaltered in both regions. These findings extend previous work by demonstrating that NBP14 preferentially influences T14 within the SN, while sparing the ST, highlighting anatomical and receptor specificity within the nigrostriatal system. These results strengthen the rationale for further investigation of NBP14 as a potential therapeutic strategy in neurodegenerative disease.