AUTHOR=Plá Virginia , Barranco Neus , Pozas Esther , Aguado Fernando 

TITLE=Amyloid-β Impairs Vesicular Secretion in Neuronal and Astrocyte Peptidergic Transmission

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=10

YEAR=2017

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00202

DOI=10.3389/fnmol.2017.00202

ISSN=1662-5099

ABSTRACT=<p>Regulated secretion of neuropeptides and neurotrophic factors critically modulates function and plasticity of synapses and circuitries. It is believed that rising amyloid-β (Aβ) concentrations, synaptic dysfunction and network disorganization underlie early phases of Alzheimer’s disease (AD). Here, we analyze the impact of soluble Aβ<sub>1–42</sub> assemblies on peptidergic secretion in cortical neurons and astrocytes. We show that neurons and astrocytes differentially produce and release carboxypeptidase E (CPE) and secretogranin III (SgIII), two dense-core vesicle (DCV) markers belonging to the regulated secretory pathway. Importantly, Aβ<sub>1–42</sub>, but not scrambled Aβ<sub>1–42</sub>, dramatically impairs basal and Ca<sup>2+</sup>-regulated secretions of endogenously produced CPE and SgIII in cultured neurons and astrocytes. Additionally, KCl-evoked secretion of the DCV cargo brain-derived neurotrophic factor (BDNF) is lowered by Aβ<sub>1–42</sub> administration, whereas glutamate release from synaptic vesicle (SVs) remains unchanged. In agreement with cell culture results, Aβ<sub>1–42</sub> effects on CPE and SgIII secretion are faithfully recapitulated in acute adult brain slices. These results demonstrate that neuronal and astrocyte secretion of DCV cargos is impaired by Aβ <italic>in vitro</italic> and <italic>in situ</italic>. Furthermore, Aβ-induced dysregulated peptidergic transmission could have an important role in the pathogenesis of AD and DCV cargos are possible candidates as cerebrospinal fluid (CSF) biomarkers.</p>