title: Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.
abstract: Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Toneff
authors.forename: Lydiane
authors.initials: L
authors.lastname: Funkelstein
authors.forename: Charles
authors.initials: C
authors.lastname: Mosier
authors.forename: Armen
authors.initials: A
authors.lastname: Abagyan
authors.forename: Michael
authors.initials: M
authors.lastname: Ziegler
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism; D019004:Galanin / Q000378:metabolism; D005731:Ganglionic Stimulants / Q000494:pharmacology; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002395:Catecholamines; D004745:Enkephalins; D005731:Ganglionic Stimulants; D009478:Neuropeptide Y; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D005576:Colforsin; D009538:Nicotine; D019004:Galanin; D000242:Cyclic AMP; D053829:Amyloid Precursor Protein Secretases; D004298:Dopamine; D009638:Norepinephrine; D004837:Epinephrine
keywords: APP; Aβ; BSA; Catecholamines; DCSV; Dense core secretory vesicles; NPY; Neuropeptides; Neurotransmitters; PBS; Regulated secretion; amyloid precursor protein; bovine serum albumin; dense core secretory vesicles; neuropeptide Y; phosphate-buffered saline; β-Amyloid; β-amyloid