AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease, characterized by memory loss and cognitive impairment. The pathology of AD includes the accumulation of beta‐amyloid (Aβ) in the extracellular space and hyper‐phosphorylation of tau in neurons. Aβ pathology has been shown to begin approximately 20 years before tau pathology and mild cognitive impairment develop in AD patients. Aβ deposits cause alterations in brain function, leading to the loss of neurons in the cerebral cortex and hippocampus in the later stages of AD. However, the cellular mechanisms by which Aβ induces AD pathology remain largely elusive. Traditionally, lower neuronal activity has been thought to contribute to the synaptic failure and cognitive impairments observed in AD. However, recent studies suggest that Aβ triggers neuronal hyperactivity during the early stages of AD. Consistent with this observation, epileptic seizures have been detected in both mouse models of AD and human patients with Alzheimer’s. Uncontrolled or severe seizures can lead to further brain damage and exacerbate the cognitive decline seen in AD. Thus, neuronal hyperactivity could be one of the contributing factors to the neuronal loss induced by Aβ. However, it is unclear how Aβ can induce neuronal hyperactivity and seizures.MethodTo evaluate seizure susceptibility, we employed kainic acid‐induced seizures in a well‐established AD mouse model, the APP/PS1 mice. To measure neuronal activity, we employed primary cortical neuron cultures treated with a scrambled or Aβ 1‐42 peptide and recorded with a multi‐electrode array (MEA) recording system. Biochemistry and molecular biology assays were performed to study molecular players associated with Aβ‐induced neuronal hyperactivity.ResultOur data showed that acute Aβ treatment induces hyperexcitability in wild‐type (WT) cortical neurons. We also confirmed a higher susceptibility to seizures in APP/PS1 mice. Lastly, we identified a postsynaptic protein that is up‐regulated and potential involved in Aβ‐triggered neuronal hyperexcitability.ConclusionIn summary, our data are expected to provide insights into the etiology of AD‐associated brain hyperactivity and potentially suggest therapeutic targets for reducing seizures during early stage of AD.