title: Pyroglutamate-amyloid-β and glutaminyl cyclase are colocalized with amyloid-β in secretory vesicles and undergo activity-dependent, regulated secretion.
abstract: OBJECTIVE
  N-truncated pyroglutamate (pGlu)-amyloid-β [Aβ(3-40/42)] peptides are key components that promote Aβ peptide accumulation, leading to neurodegeneration and memory loss in Alzheimer's disease. Because Aβ deposition in the brain occurs in an activity-dependent manner, it is important to define the subcellular organelle for pGlu-Aβ(3-40/42) production by glutaminyl cyclase (QC) and their colocalization with full-length Aβ(1-40/42) peptides for activity-dependent, regulated secretion. Therefore, the objective of this study was to investigate the hypothesis that pGlu-Aβ and QC are colocalized with Aβ in dense-core secretory vesicles (DCSV) for activity-dependent secretion with neurotransmitters.
  
  
  METHODS
  Purified DCSV were assessed for pGlu-Aβ(3-40/42), Aβ(1-40/42), QC, and neurotransmitter secretion. Neuron-like chromaffin cells were analyzed for cosecretion of pGlu-Aβ, QC, Aβ, and neuropeptides. The cells were treated with a QC inhibitor, and pGlu-Aβ production was measured. Human neuroblastoma cells were also examined for pGlu-Aβ and QC secretion.
  
  
  RESULTS
  Isolated DCSV contain pGlu-Aβ(3-40/42), QC, and Aβ(1-40/42) with neuropeptide and catecholamine neurotransmitters. Cellular pGlu-Aβ and QC undergo activity-dependent cosecretion with Aβ and enkephalin and galanin neurotransmitters. The QC inhibitor decreased the level of secreted pGlu-Aβ. The human neuroblastoma cells displayed regulated secretion of pGlu-Aβ that was colocalized with QC.
  
  
  CONCLUSIONS
  pGlu-Aβ and QC are present with Aβ in DCSV and undergo activity-dependent, regulated cosecretion with neurotransmitters.
authors.affiliation: Fraunhofer IZJ-MWT, Halle, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Lydiane
authors.initials: L
authors.lastname: Funkelstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.forename: Charles
authors.initials: C
authors.lastname: Mosier
authors.forename: Michael
authors.initials: M
authors.lastname: Ziegler
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
mesh_terms: D019881:Aminoacyltransferases / Q000032:analysis / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002837:Chromaffin Granules / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism; D022142:Secretory Vesicles / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase; D011761:Pyrrolidonecarboxylic Acid