Effect of Aβ Oligomers on Neuronal APP Triggers a Vicious Cycle Leading to the Propagation of Synaptic Plasticity Alterations to Healthy Neurons.
Amyloid beta-Peptides
/ pharmacology
Amyloid beta-Protein Precursor
/ antagonists & inhibitors
Animals
Antibodies, Blocking
/ pharmacology
Cerebral Cortex
/ drug effects
Extracellular Space
/ drug effects
Hippocampus
/ drug effects
Histidine
/ metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuronal Plasticity
/ drug effects
Neurons
/ drug effects
Patch-Clamp Techniques
Primary Cell Culture
Synapses
/ drug effects
Synaptic Transmission
/ drug effects
APP KO mice
APP processing
Alzheimer's disease
NMDA-dependent synaptic transmission
synaptic plasticity
β- and γ-secretase inhibition
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
21
10
2019
revised:
04
03
2020
accepted:
03
04
2020
pubmed:
24
5
2020
medline:
24
11
2020
entrez:
24
5
2020
Statut:
ppublish
Résumé
Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-β oligomers (Aβos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aβos affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Aβos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Aβos reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that Aβos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aβos. Intracellular Aβos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aβos. Furthermore, we provide evidence that following APP processing, extracellular release of Aβos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Aβos in AD, while intracellular Aβos alter synaptic function, extracellular Aβos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.
Identifiants
pubmed: 32444385
pii: JNEUROSCI.2501-19.2020
doi: 10.1523/JNEUROSCI.2501-19.2020
pmc: PMC7329309
doi:
Substances chimiques
APP protein, mouse
0
Amyloid beta-Peptides
0
Amyloid beta-Protein Precursor
0
Antibodies, Blocking
0
Histidine
4QD397987E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5161-5176Informations de copyright
Copyright © 2020 the authors.
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