Oxidative Stress Triggers a Pivotal Peptide Linked to Alzheimer's Disease.

An aberrant recapitulation of a developmental mechanism driven by a 14 mer peptide ('T14') derived from acetylcholinesterase (AChE) has been implicated in Alzheimer's disease. T14 was suggested as an upstream driver of neurodegeneration due to its ability to stimulate the production of phosphorylated tau and amyloid beta. The activation of this mechanism in adulthood is thought to be brought upon by insult to the primarily vulnerable subcortical nuclei. Here, we show that oxidative stress, induced by high glucose and confirmed by an analysis of antioxidant enzyme mRNA expression, increased the levels of T14 peptide in PC12 cells. This increase in T14 corresponded with an increase in the mRNA expression of AChE and a decrease in the cell viability. The increase in T14 could be blocked by the cyclic form of T14, NBP14, which prevented any cytotoxic effects. These observations suggest that oxidative stress can directly trigger the inappropriate activation of T14 in the adult brain through the upregulation of Ache mRNA.