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Precision Mapping of Amyloid-β Binding Reveals Perisynaptic Localization and Spatially Restricted Plasticity Deficits. | LitMetric

AI Article Synopsis

  • Secreted amyloid-β (Aβ) peptides form toxic oligomers that are linked to synaptic problems in Alzheimer's disease by blocking learning and memory mechanisms.
  • Research using advanced imaging techniques revealed that Aβ oligomers bind to neurons not at the synaptic cleft, but instead create distinct clusters around the postsynaptic membrane and even attach to presynaptic terminals.
  • The binding of Aβ oligomers is associated with deficits in synaptic plasticity, indicating localized signaling disruptions that contribute to synaptic dysfunction, paving the way for future research on receptors and mechanisms involved in this process.

Article Abstract

Secreted amyloid-β (Aβ) peptide forms neurotoxic oligomeric assemblies thought to cause synaptic deficits associated with Alzheimer's disease (AD). Soluble Aβ oligomers (Aβo) directly bind to neurons with high affinity and block plasticity mechanisms related to learning and memory, trigger loss of excitatory synapses and eventually cause cell death. While Aβo toxicity has been intensely investigated, it remains unclear precisely where Aβo initially binds to the surface of neurons and whether sites of binding relate to synaptic deficits. Here, we used a combination of live cell, super-resolution and ultrastructural imaging techniques to investigate the kinetics, reversibility and nanoscale location of Aβo binding. Surprisingly, Aβo does not bind directly at the synaptic cleft as previously thought but, instead, forms distinct nanoscale clusters encircling the postsynaptic membrane with a significant fraction also binding presynaptic axon terminals. Synaptic plasticity deficits were observed at Aβo-bound synapses but not closely neighboring Aβo-free synapses. Thus, perisynaptic Aβo binding triggers spatially restricted signaling mechanisms to disrupt synaptic function. These data provide new insight into the earliest steps of Aβo pathology and lay the groundwork for future studies evaluating potential surface receptor(s) and local signaling mechanisms responsible for Aβo binding and synapse dysfunction.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8687484PMC
http://dx.doi.org/10.1523/ENEURO.0416-21.2021DOI Listing

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