Suppression of epileptiform activity by treatment with antiepileptic drugs or by genetic ablation of tau in aged human amyloid precursor protein transgenic mice

Abstract

AbstractBackgroundNeural network dysfunction, including subclinical epileptiform activity, occurs in a substantial proportion of Alzheimer’s disease (AD) patients and related mouse models. Treatment with the anti‐epileptic drug levetiracetam (LEV) or genetically ablating the protein tau effectively reduces epileptiform activity and behavioral abnormalities in human amyloid precursor protein (hAPP) transgenic mice. These findings support the hypothesis that network dysfunction may promote cognitive deficits in AD. While LEV treatment and tau reduction have beneficial effects in young adult hAPP mice, it is not known whether there are similarly beneficial effects in aged mice, whose pathological condition may be more similar to that of AD. To address this gap, we tested the efficacy of LEV treatment and tau reduction in preventing or reversing network, immune and cognitive dysfunctions in aged hAPP mice.MethodWe treated 22–26‐month‐old, male hAPP mice and age‐ and sex‐matched wildtype (WT) controls with placebo or LEV for four months using chow formulations. To genetically ablate tau, we generated a cohort of male and female Mapt +/+ and Mapt –/– mice that did or did not express hAPP. Mice were assessed by electroencephalography (EEG) and behavior. Brain tissues were subjected to transcriptome analysis and immunohistochemistry.ResultsIntracranial EEG recordings revealed that placebo‐treated hAPP mice had aberrantly increased epileptiform activity as compared with placebo‐treated WT controls and that this neural network dysfunction was effectively suppressed by chronic LEV treatment or by tau ablation. Both manipulations reduced behavioral deficits detected in aged hAPP mice. Hippocampal levels of inflammation‐related transcripts were analyzed using a NanoString Neuroinflammation panel. Compared to WT mice, more inflammation‐related transcripts were increased than decreased in hAPP mice. LEV treatment reversed and tau ablation prevented the altered expression of many inflammation‐related genes in the hippocampus of hAPP mice. Immunolabeling tissues with an antibody against human Aβ revealed extensive amyloid deposition in aged hAPP mice but LEV treatment nor tau ablation changed the number or size of amyloid plaques.ConclusionLEV treatment and tau ablation reduce network, immune and cognitive dysfunctions, but not amyloid load, in aged hAPP mice. These findings demonstrate that LEV treatment and tau reduction counteract AD‐related pathophysiological abnormalities independent of age.