We have new evidence of the influence of APOE genotype in determining the resilience of neurons weathering glutamate-induced hyperexcitation in temporal lobe epilepsy; that is, compared to other APOE genotypes, APOE epsilon 3,3 genotype is associated with larger more robust neurons, as evidenced by less DNA damage and higher levels of the neuronal acute phase proteins beta APP and ApoE. This supports our previous results that glutamate induction of neuronal beta APP expression is regulated in an isoform specific manner by ApoE, ApoE3 better than ApoE4. We propose that APOE genotype is a key factor in the regulation of neuronal responses to the glutamate-induced neuronal hyperexcitation in epilepsy such that allelic combinations with APOE epsilon 4 are less advantageous than those without. To examine the validity of this hypothesis, we employed cell and molecular techniques to define and characterize glial and neuronal responses, using surgical waste from temporal lobe tissues of 92 epilepsy patients (58 males and 34 females coming to surgery for intractable drug-resistant epilepsy: 1 APOE epsilon 2,2, 12 APOE epsilon 2,3, 2 APOE epsilon 2,4, 53 APOE epsilon 3,3, 17 APOE epsilon 3,4, and 7 APOE epsilon 4,4. Age at surgery ranged from 3 months to 71 years. Our study aims were built upon our findings relating glutamate hyperexcitation, cytokine expression, and interactions between beta APP and ApoE in cell culture, in animal models, and in AD. Our first target was to determine glial cells responses in tissue of epilepsy patients carrying one of the six APOE allelic combinations. Our next step was to determine the role of each of the APOE allelic combinations in the modulation of neuronal responses including beta APP and ApoE expression, and cellular, synaptic, and DNA integrity. Our third aim was to examine the influence of APOE genotypes on epilepsy-induced neuropathological change. Our results provide greater understanding of how each of the combinations of APOE genotype relate to neuronal and glial responses in epilepsy and its promotion of neurodegenerative consequences.
|Advisor:||Griffin, Sue T.|
|Commitee:||Al-Chaer, Elie D., Barger, Steven, Griffin, Sue T., Kiaei, Mahmoud, Mrak, Robert E.|
|School:||University of Arkansas for Medical Sciences|
|Department:||Neurobiology and Developmental Science|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 74/09(E), Dissertation Abstracts International|
|Keywords:||Apolipoprotein E, Epilepsy, Glutamate, Hyperexcitation|
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