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

Background and Aims: N-truncated pyroglutamate (pGlu)-amyloid-beta [A beta(3-40/42)] peptides are key components that promote A beta peptide accumulation, leading to neurodegeneration and memory loss in Alzheimer's disease. Because A beta deposition in the brain occurs in an activity-dependent manner, it is important to define the subcellular organelle for pGlu-A beta(3-40/42) production by glutaminyl cyclase (QC) and their colocalization with full-length A beta(1-40/42) peptides for activity-dependent, regulated secretion. Therefore, the objective of this study was to investigate the hypothesis that pGlu-A beta and QC are colocalized with A beta in dense-core secretory vesicles (DCSV) for activity-dependent secretion with neurotransmitters. Methods: Purified DCSV were assessed for pGlu-A beta(3-40/42), A beta(1-40/42), QC, and neurotransmitter secretion. Neuron-like chromaffin cells were analyzed for cosecretion of pGlu-A beta, QC, A beta, and neuropeptides. The cells were treated with a QC inhibitor, and pGlu-A beta production was measured. Human neuroblastonna cells were also examined for pGlu-A beta and QC secretion. Results: Isolated DCSV contain pGlu-A beta(3-40/42), QC, and A beta(1-40/42) with neuropeptide and catecholamine neurotransmitters. Cellular pGlu-A beta and QC undergo activity-dependent cosecretion with A beta and enkephalin and galanin neurotransmitters. The QC inhibitor decreased the level of secreted pGlu-A beta. The human neuroblastoma cells displayed regulated secretion of pGlu-A beta that was colocalized with QC. Conclusions: pGlu-A beta and QC are present with A beta in DCSV and undergo activity-dependent, regulated cosecretion with neurotransmitters. (C) 2014 S. Karger AG, Basel