PSD-95 protects synapses from β-amyloid

Beta-amyloid (Aβ) 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 Aβ on synapses. The protective effect persists in tissue lacking the AMPA receptor subunit GluA1, which prevents the confounding synaptic potentiation by increased PSD-95. Aβ 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 Aβ-induced effects on the NMDAR CTD conformation, its interaction with PP1, and synaptic weakening. Our results indicate that increased PSD-95 protects synapses from Aβ toxicity, suggesting that low levels of synaptic PSD-95 may be a molecular sign indicating synapse vulnerability to Aβ. Importantly, pharmacological inhibition of its depalmitoylation increases PSD-95 at synapses and rescues deficits caused by Aβ, possibly opening a therapeutic avenue against Alzheimer’s disease. [Display omitted] •Elevated PSD-95 prevents Ab-induced synaptic depression•Aβ-triggered metabotropic NMDA receptor signaling is blocked by elevated PSD-95•Synapses with high amounts of endogenous PSD-95 are protected from Aβ•Drug inhibition of PSD-95 depalmitoylation reverses Aβ effects on synapses The molecular mechanisms by which beta-amyloid (Aβ) damages synapses are poorly understood. Dore et al. show that increasing PSD-95 synaptic contentprotects synapses from Ab-induced synaptic deficits by reducing NMDA receptor metabotropic function.