Precision Mapping of Amyloid-ß Binding Reveals Perisynaptic Localization and Spatially Restricted Plasticity Deficits.
eNeuro
; 8(6)2021.
Article
em En
| MEDLINE
| ID: mdl-34789478
ABSTRACT
Secreted amyloid-ß (Aß) peptide forms neurotoxic oligomeric assemblies thought to cause synaptic deficits associated with Alzheimer's disease (AD). Soluble Aß oligomers (Aßo) 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 Aßo toxicity has been intensely investigated, it remains unclear precisely where Aßo 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 Aßo binding. Surprisingly, Aßo 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 Aßo-bound synapses but not closely neighboring Aßo-free synapses. Thus, perisynaptic Aßo binding triggers spatially restricted signaling mechanisms to disrupt synaptic function. These data provide new insight into the earliest steps of Aßo pathology and lay the groundwork for future studies evaluating potential surface receptor(s) and local signaling mechanisms responsible for Aßo binding and synapse dysfunction.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Revista:
ENeuro
Ano de publicação:
2021
Tipo de documento:
Article