Abstract
BackgroundEpilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype.MethodsTissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.ResultsTissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17).ConclusionsOur findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).Please see related article: http://www.biomedcentral.com/1741-7015/10/36
Highlights
Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation
Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and confers less risk of AD (Alzheimer’s disease)
Our findings indicate that the APOE ε3,3 genotype confers a neuroprotective advantage over the APOE ε4,4 genotype, in the setting of intractable epilepsy with its accompanying hyperexcitability-induced neuronal damage, glial activation and excessive expression of the proinflammatory cytokine interleukin-1 alpha (IL-1a)
Summary
Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. A role for glial activation with excess expression of cytokines in epilepsy pathogenesis was first recognized as enlargement of Neuronal stress, such as the hyperexcitability induced by glutamate in epilepsy, elevates neuronal expression of bAPP and release of sAPP, which activates microglia and induces excess IL-1 production This elevation in IL-1 production is attenuated by ApoE 3, but not ApoE 4 [7]. Tissue samples from temporal lobes resected from epilepsy patients carrying two APOE ε3 alleles were examined regarding an association between inheritance of these alleles and determinants of neuronal resilience These determinants included the ability of neurons to mount appropriate acute phase responses, including increases in bAPP and ApoE, as well as management of DNA damage, maintenance of morphological integrity and glial activation. Our findings indicate that the APOE ε3,3 genotype confers a neuroprotective advantage over the APOE ε4,4 genotype, in the setting of intractable epilepsy with its accompanying hyperexcitability-induced neuronal damage, glial activation and excessive expression of the proinflammatory cytokine IL-1a
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