Pyroglutamate-Amyloid-v and Glutaminyl Cyclase are Colocalized with Amyloid-v in Secretory Vesicles and Undergo Activity-Dependent, Regulated Secretion

Background and Aims: N-truncated pyroglutamate (pGlu)-amyloid-v [Av(3-40/42)] peptides are key components that promote Av peptide accumulation, leading to neurodegeneration and memory loss in Alzheimer's disease. Because Av deposition in the brain occurs in an activity-dependent manner, it is important to define the subcellular organelle for pGlu-Av(3-40/42) production by glutaminyl cyclase (QC) and their colocalization with full-length Av(1-40/42) peptides for activity-dependent, regulated secretion. Therefore, the objective of this study was to investigate the hypothesis that pGlu-Av and QC are colocalized with Av in dense-core secretory vesicles (DCSV) for activity-dependent secretion with neurotransmitters. Methods: Purified DCSV were assessed for pGlu-Av(3-40/42), Av(1-40/42), QC, and neurotransmitter secretion. Neuron-like chromaffin cells were analyzed for cosecretion of pGlu-Av, QC, Av, and neuropeptides. The cells were treated with a QC inhibitor, and pGlu-Av production was measured. Human neuroblastoma cells were also examined for pGlu-Av and QC secretion. Results: Isolated DCSV contain pGlu-Av(3-40/42), QC, and Av(1-40/42) with neuropeptide and catecholamine neurotransmitters. Cellular pGlu-Av and QC undergo activity-dependent cosecretion with Av and enkephalin and galanin neurotransmitters. The QC inhibitor decreased the level of secreted pGlu-Av. The human neuroblastoma cells displayed regulated secretion of pGlu-Av that was colocalized with QC. Conclusions: pGlu-Av and QC are present with Av in DCSV and undergo activity-dependent, regulated cosecretion with neurotransmitters.