Pyroglutamate-amyloid-β and glutaminyl cyclase are colocalized with amyloid-β in secretory vesicles and undergo activity-dependent, regulated secretion.

Abstract

BACKGROUND AND AIMS:

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: Holger Cynis, Lydiane Funkelstein, Thomas Toneff, Charles Mosier, Michael Ziegler, Birgit Koch, Hans-Ulrich Demuth, Vivian Hook
• Journal: Neuro-degenerative diseases (Neurodegener Dis) Vol. 14 Issue 2 Pg. 85-97 ( 2014) ISSN: 1660-2862 [Electronic] Switzerland
• PMID: 24943989 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 S. Karger AG, Basel.

Chemical References

• Amyloid beta-Peptides
• Aminoacyltransferases
• glutaminyl-peptide cyclotransferase
• Pyrrolidonecarboxylic Acid

Topics

• Aminoacyltransferases (analysis, metabolism)
• Amyloid beta-Peptides (analysis, chemistry, metabolism)
• Cell Line, Tumor
• Chromaffin Granules (chemistry, metabolism, ultrastructure)
• Humans
• Pyrrolidonecarboxylic Acid (metabolism)
• Secretory Vesicles (chemistry, metabolism, ultrastructure)