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

Yeeun Yook, Kwan Young Lee, Eunyoung Kim, Simon Lizarazo, Xinzhu Yu, Nien Pei Tsai

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1233-1255
Number of pages23
JournalEMBO Reports
Issue number3
Early online dateFeb 27 2024
StatePublished - Mar 12 2024


  • Alzheimer’s Disease
  • AMPA Receptors
  • Mdm2
  • PSD-95
  • Seizure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics


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