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

Abstract

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 Aβ1–42 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, Aβ1–42, but not scrambled Aβ1–42, dramatically impairs basal and Ca2+-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 Aβ1–42 administration, whereas glutamate release from synaptic vesicle (SVs) remains unchanged. In agreement with cell culture results, Aβ1–42 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 in vitro and in situ. 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.

Expression Pattern of the LacZ Reporter in Secretogranin III Gene-trapped Mice

“…29 Because CPE and SgIII are essential in the processing and targeting of neuropeptides and neurotrophins, their participation in the pathological progression of AD may be suggested. 30 SgIII was expressed in the retina, where it acted as an angiogenic factor in diabetic retinopathy. 31,32 Furthermore, SgIII has been suggested to be involved in signal transduction in neurotoxin-induced apoptosis in dopaminergic neuroblasts.…”

Amyloid-β Oligomers Induce Only Mild Changes to Inhibitory Bouton Dynamics

“…It is previously reported that Aβ can induce impairments in release of neurotransmitter or peptides from presynaptic terminals [ 33–35 ], including at inhibitory synapses [ 21 ], but it is unknown if this will affect synaptic dynamics. Presynaptic defects may be specifically important in AβPP-expressing GABAergic neurons [ 25, 26 ], which axons are presumably exposed to the highest Aβ levels.…”

“…Inhibitory boutons can rapidly appear and disappear along the axon in response to changes in activity or molecular signals [ 14, 30–32 ]. Aβ toxicity has been reported to specifically induce presynaptic impairments [ 33–36 ], including at inhibitory synapses [ 21 ], but it is unknown if Aβ interferes with synaptic dynamics in inhibitory axons.…”

Amyloid-β Impairs Dendritic Trafficking of Golgi-Like Organelles in the Early Phase Preceding Neurite Atrophy: Rescue by Mirtazapine

“…We propose that mirtazapine can exert protective effects against Aβ injury by acting on dendritic trafficking mechanisms that are required for the proper functioning of the anterograde secretory pathway as well as retrograde retromer trafficking in dendrites. Previous studies have shown that Aβ oligomers and neuroinflammation associated with AD impair axonal and dendritic retromer trafficking of BDNF, causing a downregulation in neurotrophin signaling, essential for neuronal development and maintenance of dendritic complexity ( Poon et al, 2011 ; Gan and Silverman, 2016 ; Seifert et al, 2016 ; Carlos et al, 2017 ; Plá et al, 2017 ). In hAPP transgenic mice, the impairment in axonal retrograde trafficking induced an aberrant retention of endosomes in distal neurites and impaired endosome-TGN and lysosomal functioning ( Tammineni et al, 2017 ).…”

“…Aberrant folding and accumulation of the amyloid-β peptide (Aβ), an hallmark of AD, causes neurite degeneration, synapse loss, and impairment in neuronal trafficking ( Serrano-Pozo et al, 2011 ; Plá et al, 2017 ). In the present study, using a live imaging approach on hippocampal neurons in culture, we investigate how Aβ 25 – 25 oligomers affect the dynamics of pGOLT-expressing vesicles indicative of Golgi-related organelles, such as Golgi outposts and satellites ( Horton and Ehlers, 2003b ; Horton et al, 2005 ; Mikhaylova et al, 2016 ).…”