PSD-95 protects synapses from ß-amyloid.
Cell Rep
; 35(9): 109194, 2021 06 01.
Article
em En
| MEDLINE
| ID: mdl-34077732
ABSTRACT
Beta-amyloid (Aß) depresses excitatory synapses by a poorly understood mechanism requiring NMDA receptor (NMDAR) function. Here, we show that increased PSD-95, a major synaptic scaffolding molecule, blocks the effects of Aß on synapses. The protective effect persists in tissue lacking the AMPA receptor subunit GluA1, which prevents the confounding synaptic potentiation by increased PSD-95. Aß modifies the conformation of the NMDAR C-terminal domain (CTD) and its interaction with protein phosphatase 1 (PP1), producing synaptic weakening. Higher endogenous levels or overexpression of PSD-95 block Aß-induced effects on the NMDAR CTD conformation, its interaction with PP1, and synaptic weakening. Our results indicate that increased PSD-95 protects synapses from Aß toxicity, suggesting that low levels of synaptic PSD-95 may be a molecular sign indicating synapse vulnerability to Aß. Importantly, pharmacological inhibition of its depalmitoylation increases PSD-95 at synapses and rescues deficits caused by Aß, possibly opening a therapeutic avenue against Alzheimer's disease.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sinapses
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Peptídeos beta-Amiloides
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Neuroproteção
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Proteína 4 Homóloga a Disks-Large
Limite:
Animals
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2021
Tipo de documento:
Article