Chronic Temporal Lobe Epilepsy Is Associated with Enhanced Alzheimer-Like Neuropathology in 3×Tg-AD Mice

Xiao Xin Yan, Yan Cai, Jarod Shelton, Si Hao Deng, Xue Gang Luo, Salvatore Oddo, Frank M. LaFerla, Huaibin Cai, Gregory M. Rose, Peter R. Patrylo

Research output: Contribution to journalArticle

28 Scopus citations

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.

Original languageEnglish (US)
Article numbere48782
JournalPloS one
Volume7
Issue number11
DOIs
StatePublished - Nov 14 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Yan, X. X., Cai, Y., Shelton, J., Deng, S. H., Luo, X. G., Oddo, S., LaFerla, F. M., Cai, H., Rose, G. M., & Patrylo, P. R. (2012). Chronic Temporal Lobe Epilepsy Is Associated with Enhanced Alzheimer-Like Neuropathology in 3×Tg-AD Mice. PloS one, 7(11), [e48782]. https://doi.org/10.1371/journal.pone.0048782