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

Xiao-Xin Yan,Frank M Laferla,Xue-Gang Luo,Yan Cai,Peter R Patrylo,Jarod Shelton,Gregory M Rose,Huaibin Cai,Si-Hao Deng,Salvatore Oddo,Joseph Najbauer

doi:10.1371/journal.pone.0048782

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.

Highlights

Alzheimer’s disease (AD) and chronic temporal lobe epilepsy (TLE) are classified as two distinct neurological disorders according to their major presenting symptoms
To determine whether TLE-induced BACE1 overexpression could promote amyloidogenic and p-tau pathology, we induced status epilepticus in 36Tg-AD mice
Pilocarpine administration does not always induce acute status epilepticus that results in chronic epilepsy in rodents

Summary

Introduction

Alzheimer’s disease (AD) and chronic temporal lobe epilepsy (TLE) are classified as two distinct neurological disorders according to their major presenting symptoms. They share many pathological features including temporal lobe atrophy, neuronal death, gliosis, neuritic alterations and inflammation [1],[2],[3],[4],[5],[6],[7],[8],[9]. Mackenzie and Miller [16] reported senile plaques in approximately 10% of surgical temporal lobe samples from TLE cases that ranged in age from 36 to 61 years and did not exhibit dementia by standard neuropsychological tests. In addition to amyloid pathology, tauopathy or phosphorylated tau (p-tau) overexpression has been reported in epileptic human brain and in animal models of epilepsy [17],[18],[19],[20],[21]

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Results

Conclusion