Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

Beta-amyloid (Aß) peptides are secreted from neurons, resulting in extracellular accumulation of Aß and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aß undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aß(1-40) and Aß(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 Aß peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aß with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aß was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, ß- and γ-secretases, that are necessary for production of Aß. Thus, Aß can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aß(1-40) and Aß(1-42) with the galanin neurotransmitter. These findings illustrate that Aß peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.