Epilepsy: neuroinflammation, neurodegeneration, and APOE genotype

Orwa Aboud,Robert E Mrak,Frederick A Boop,W Sue T Griffin

doi:10.1186/2051-5960-1-41

Abstract

BackgroundPrecocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ϵ4,4 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 β (Aβ) precursor protein (βAPP), Aβ, apolipoprotein E (ApoE), S100B, interleukin-1α and β, and α and β secretases; and on markers of neuronal stress, including DNA/RNA damage and caspase 3 expression.ResultsAllelic combinations of APOE influenced each epilepsy-related neuronal and glial response measured as well as neuropathological change. APOE ϵ3,3 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 ϵ2 allele, none had Aβ plaques; their neuronal sizes, like those with APOE ϵ3,3 genotype were larger than those with other genotypes. APOE ϵ4,4 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.ConclusionsOur 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.

Highlights

Precocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ε4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome
A comparison between surgical waste tissues from patients undergoing anterior temporal lobectomy surgery for drug-resistant intractable epilepsy showed that APOE ε3,3 and APOE ε4,4 genotypes dramatically alter the expression of β (Aβ) precursor protein (βAPP) and of IL-1 such that the APOE ε3 allele is more effective with regard to the maintenance of appropriate neuronal acute phase responses that favor neuronal viability than is APOE ε4 [2]
APOE genotype modulation of glial responses in epilepsy Glial numbers in a given cross-sectional cortical area Patients in Group 1 had the lowest number of microglia per neuron: 82% of the neurons had less than two adjacent microglia

Summary

Introduction

Precocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ε4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome. Traumatic brain injury (TBI), which is a major risk factor for the development of epilepsy [5], is associated with increased risk for later development of AD, and, in both cases, the risk of development of AD is greater with inheritance of In both purified rodent neuronal cell cultures and cultures of the human neuroblastoma cell line NT2, excess glutamate induces marked increases in the expression of the neuronal acute phase response protein βAPP, and in the release of its secreted fragment sAPPα [11], which is a powerful inducer of glial activation and increased production and release of the proinflammatory cytokine IL-1β [12]. This is relevant to the possibility that the decrease in the ability of ApoE4 compared with ApoE3 to elevate synthesis of the neuronal acute phase protein βAPP [15] is responsible for less sAPPα release, resulting in diminished neuronal repair and survival [16]

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