title: Chronic temporal lobe epilepsy is associated with enhanced Alzheimer-like neuropathology in 3×Tg-AD mice.
abstract: The comorbidity between epilepsy and Alzheimer's disease (AD) is a topic of growing interest. Senile plaques and tauopathy are found in epileptic human temporal lobe structures, and individuals with AD have an increased incidence of spontaneous seizures. However, why and how epilepsy is associated with enhanced AD-like pathology remains unknown. We have recently shown β-secretase-1 (BACE1) elevation associated with aberrant limbic axonal sprouting in epileptic CD1 mice. Here we sought to explore whether BACE1 upregulation affected the development of Alzheimer-type neuropathology in mice expressing mutant human APP, presenilin and tau proteins, the triple transgenic model of AD (3×Tg-AD). 3×Tg-AD mice were treated with pilocarpine or saline (i.p.) at 6-8 months of age. Immunoreactivity (IR) for BACE1, β-amyloid (Aβ) and phosphorylated tau (p-tau) was subsequently examined at 9, 11 or 14 months of age. Recurrent convulsive seizures, as well as mossy fiber sprouting and neuronal death in the hippocampus and limbic cortex, were observed in all epileptic mice. Neuritic plaques composed of BACE1-labeled swollen/sprouting axons and extracellular AβIR were seen in the hippocampal formation, amygdala and piriform cortices of 9 month-old epileptic, but not control, 3×Tg-AD mice. Densities of plaque-associated BACE1 and AβIR were elevated in epileptic versus control mice at 11 and 14 months of age. p-Tau IR was increased in dentate granule cells and mossy fibers in epileptic mice relative to controls at all time points examined. Thus, pilocarpine-induced chronic epilepsy was associated with accelerated and enhanced neuritic plaque formation and altered intraneuronal p-tau expression in temporal lobe structures in 3×Tg-AD mice, with these pathologies occurring in regions showing neuronal death and axonal dystrophy.
authors.affiliation: Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China. yanxiaoxin@csu.edu.cn
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Yan
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.forename: Jarod
authors.initials: J
authors.lastname: Shelton
authors.forename: Si-Hao
authors.initials: SH
authors.lastname: Deng
authors.forename: Xue-Gang
authors.initials: XG
authors.lastname: Luo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
authors.forename: Frank M
authors.initials: FM
authors.lastname: Laferla
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rose
authors.forename: Peter R
authors.initials: PR
authors.lastname: Patrylo
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010862:Pilocarpine; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016875:tau Proteins; D010862:Pilocarpine; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse