Decoding the molecular and structural determinants of the neurokinin A and Aβ1-42 peptide cross-interaction in the amyloid cascade pathway

Tachykinins are short neuropeptides, such as substance P and neurokinin B, that have been shown to interact with Alzheimer's β-amyloid (Aβ) peptide. Neurokinin A (NKA) is a secreted tachykinin neuropeptide that binds to neurokinin receptors and with an emerging role in the brain-gut axis. NKA shares the brain niche with Aβ; thus, we investigate whether and how NKA and Aβ peptide interact. We have used a combination of computational and experimental biophysics to assess the interaction of both peptides <i>in vitro</i>. Using Phe-to-Trp substitution, we have shown that Phe in the FXGLM signature in NKA is important for such interaction and for the modulation of the Aβ peptide amyloid cascade. Besides, cellular experiments have shown that the NKA-Aβ interaction decreases the Aβ peptide toxicity. Altogether, our work raises the intriguing possibility that NKA balance and the NKA-Aβ peptide interplay are relevant in the aggregation process in Alzheimer's disease.