A Novel 14mer Peptide Inhibits Autophagic Flux via Selective Activation of the mTORC1 Signalling Pathway: Implications for Alzheimer’s Disease

During development, a 14mer peptide, T14, modulates cell growth via the α-7 nicotinic acetylcholine receptor (α7 nAChR). However, this process could become excitotoxic in the context of the adult brain, leading to pathologies such as Alzheimer's disease (AD). Recent work shows that T14 acts selectively via the mammalian target of rapamycin complex 1 (mTORC1). This pathway is essential for normal development but is overactive in AD. The triggering of mTORC1 has also been associated with the suppression of autophagy, commonly observed in ageing and neurodegeneration. We therefore investigated the relationship between T14 and autophagic flux in tissue cultures, mouse brain slices, and human Alzheimer's disease hippocampus. Here, we demonstrate that T14 and p-mTOR s2448 expression significantly increases in AD human hippocampus, which was associated with the gradual decrease in the autophagosome number across Braak stages. During development, the reduction in T14 positively correlated with pTau (Ser202, Thr205) and two selective autophagy receptors: p62 and optineurin. In vitro studies also indicated that T14 increases p-mTOR s2448 expression, resulting in the aggregation of polyubiquinated substances. The effective blockade of T14 via its cyclic variant, NBP14, has been validated in vitro, in vivo, and ex vivo. In this study, NBP14 significantly attenuated p-mTOR s2448 expression and restored normal autophagic flux, as seen with rapamycin. We conclude that T14 acts at the α-7 receptor to selectively activate the mTORC1 pathway and consequently inhibit autophagic flux. Hence, this study describes a further step in the process by which T14 could drive neurodegeneration.