Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization
Copyright policy )Amyloid-β Oligomers Interact with Neurexin and Diminish Neurexin-mediated Excitatory Presynaptic Organization
AbstractAlzheimer’s disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, AβOs diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging revealed that AβO treatment reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology in AD.
- Montreal Neurological Institute and Hospital Canada
- University of Montreal Canada
- Montreal Clinical Research Institute Canada
- McGill University Canada
Amyloid beta-Peptides, Cell Adhesion Molecules, Neuronal, Presynaptic Terminals, Gene Expression, Membrane Proteins, Nerve Tissue Proteins, Article, Axons, Cell Line, Alternative Splicing, Disease Models, Animal, Mice, Alzheimer Disease, COS Cells, Chlorocebus aethiops, Animals, Humans, Protein Interaction Domains and Motifs, Protein Multimerization, Cells, Cultured, Protein Binding
Amyloid beta-Peptides, Cell Adhesion Molecules, Neuronal, Presynaptic Terminals, Gene Expression, Membrane Proteins, Nerve Tissue Proteins, Article, Axons, Cell Line, Alternative Splicing, Disease Models, Animal, Mice, Alzheimer Disease, COS Cells, Chlorocebus aethiops, Animals, Humans, Protein Interaction Domains and Motifs, Protein Multimerization, Cells, Cultured, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).35 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!