The role of β-amyloid peptides in kainic acid-induced toxicity and its implications in Mesial Temporal Lobe Epilepsy

  • Author / Creator
    Ourdev, Dimitar
  • Kainic acid is a non-degradable analogue of the excitatory neurotransmitter glutamate that, when injected systemically into adult rats, can trigger seizures and progressive neuronal loss in a manner that mirrors the neuropathology of human mesial temporal lobe epilepsy (MTLE), most prevalent form of partial epilepsy. However, the biomolecular mechanisms responsible for the neuronal loss that occurs as a consequence of this treatment remain elusive. Recent studies from our lab have shown that kainic acid administration can lead to increased levels/processing of amyloid precursor protein (APP) in activated astrocytes leading to enhanced production of amyloid-β (Aβ) peptides, which are known to play a critical role in the neurodegeneration observed in Alzheimer’s disease. At present, however, the functional consequences of Aβ peptides on kainic acid-induced loss of neurons remain unclear. Thus, in this study, we seek to establish the potential role of kainic acid-induced astrocytic Aβ peptides on the degeneration of neurons. Our results show that kainic acid treatment of human U373 astrocytoma and rat primary astrocyte cells yields increased levels/processing of APP, resulting in enhanced Aβ production/secretion without compromising cell viability. Additionally, we reveal that kainic acid induces neuronal loss more in neuronal/astrocyte co-cultures than pure neuronal cultures, and this is attenuated by precluding Aβ production. Furthermore, using selective ionotropic glutamate receptor antagonists, we show that the kainate receptor is specifically responsible for facilitating enhanced amyloidogenesis in astrocytes, thus implying an important role for this underexplored receptor in a disease context. These results suggest that Aβ peptides derived from astrocytes may have a role in kainic acid-induced neurodegeneration. Since administering kainic acid can recapitulate the main pathological features of MTLE, it is possible that the mechanisms similar to those observed in this study may also be responsible for the degeneration of neurons in this disease.

  • Subjects / Keywords
  • Graduation date
    Fall 2017
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.