Epilepsy: neuroinflammation, neurodegeneration, and APOE genotype

Background: Precocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE epsilon 4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome. Frozen and paraffin-embedded tissue samples resected from superior temporal lobes of 92 patients undergoing temporal lobectomies as a treatment for medication-resistant temporal lobe epilepsy were used in this study. To determine if epilepsy-related changes reflect those in another neurological condition, analogous tissue samples harvested from 10 autopsy-verified Alzheimer brains, and from 10 neurologically and neuropathologically normal control patients were analyzed using immunofluorescence histochemistry, western immunoblot, and real-time PCR to determine genotype effects on neuronal number and size, neuronal and glial expressions of amyloid beta (A beta) precursor protein (beta APP), A beta, apolipoprotein E (ApoE), S100B, interleukin-1 alpha and beta, and a and beta secretases; and on markers of neuronal stress, including DNA/RNA damage and caspase 3 expression. Results: Allelic combinations of APOE influenced each epilepsy-related neuronal and glial response measured as well as neuropathological change. APOE epsilon 3,3 conferred greatest neuronal resilience denoted as greatest production of the acute phase proteins and low neuronal stress as assessed by DNA/RNA damage and caspase-3 expression. Among patients having an APOE epsilon 2 allele, none had A beta plaques; their neuronal sizes, like those with APOE e3,3 genotype were larger than those with other genotypes. APOE epsilon 4,4 conferred the weakest neuronal resilience in epilepsy as well as in Alzheimer patients, but there were no APOE genotype-dependent differences in these parameters in neurologically normal patients. Conclusions: Our findings provide evidence that the strength of the neuronal stress response is more related to patient APOE genotype than to either the etiology of the stress or to the age of the patient, suggesting that APOE genotyping may be a useful tool in treatment decisions.