Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology

Accumulation of amyloid-beta (Aβ) can lead to the formation of aggregates that contribute to neurodegeneration in Alzheimer’s disease (AD). Despite globally reduced neural activity during AD onset, recent studies have suggested that Aβ induces hyperexcitability and seizure-like activity during the early stages of the disease that ultimately exacerbate cognitive decline. However, the underlying mechanism is unknown. Here, we reveal an Aβ-induced elevation of postsynaptic density protein 95 (PSD-95) in cultured neurons in vitro and in an in vivo AD model using APP/PS1 mice at 8 weeks of age. Elevation of PSD-95 occurs as a result of reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). The elevation of PSD-95 is consistent with the facilitation of excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and reduces seizure activity in APP/PS1 mice. Our results demonstrate a mechanism underlying elevated seizure activity during early-stage Aβ pathology and suggest that PSD-95 could be an early biomarker and novel therapeutic target for AD. Synopsis Neuronal hyperactivity and elevated susceptibility to seizures have been observed in early stage of Alzheimer’s disease. Accumulation of Aβ leads to an elevation of excitatory synapse numbers and seizure susceptibility, which can be ameliorated by inhibition of PSD-95. Post-synaptic density protein 95 (PSD-95) is elevated in young APP/PS1 mice as well as cultured cortical neurons treated with synthetic Aβ peptides. Elevated PSD-95 is caused by its reduced ubiquitination resulting from Akt-dependent phosphorylation of E3 ubiquitin ligase Mdm2. Genetically inhibiting PSD-95 reduces Aβ-induced elevation of excitatory synapse numbers. Genetically inhibiting PSD-95 ameliorates seizure response in APP/PS1 mice as well as wildtype mice injected with synthetic Aβ peptides. Neuronal hyperactivity and elevated susceptibility to seizures have been observed in early stage of Alzheimer’s disease. Accumulation of Aβ leads to an elevation of excitatory synapse numbers and seizure susceptibility, which can be ameliorated by inhibition of PSD-95.