Increased Epileptiform EEG Activity and Decreased Seizure Threshold in Arctic APP Transgenic Mouse Model of Alzheimer's Disease

Abstract

Several Alzheimer model mice carrying transgenic amyloid precursor protein (APP) with the Swedish mutation have been reported to exhibit spontaneous seizures and/or increased epileptiform EEG activity. The primary cause for the epilepsy phenotype is still under debate. In contrast to mice with APPswe mutation that develop extracellular amyloid plaques, mice with APP Arctic mutation (E693G) have no bias toward β-secretase cleavage and display intracellular amyloid deposits but not plaques. We conducted a systematic long-term video-EEG recording in three two-week sessions on 21 APParc and 11 wild-type control mice between 3.5 and 8 months of age. Spontaneous seizures were not detected more often in APParc mice than in their wild-type control mice. Long (1 - 5 s) epileptiform discharges were occasionally detected in both APParc and wild-type mice, but short (0.5 - <1 s) epileptiform discharges were more common in APParc mice than in wild-types. However, they were far less frequent than in 6 APPswe/PS1dE9 mice recorded in parallel. In pentylenetetrazole test for seizure susceptibility, APParc mice displayed a shorter latency to sharp-wave discharges than wildtype mice but no increase in seizure duration. These data speak for a relatively mild epilepsy phenotype in APParc mice compared to APPswe mice despite even higher extent of APP overexpression. Thus extracellular amyloid plaques or increased β-secretase cleavage products appear important for the epilepsy phenotype in APPswe mice.

Neurodegenerative pathways as targets for acquired epilepsy therapy development

“…Consistently with the aforementioned evidence, different mice models that overexpress APP also show hyperexcitation in individual neurons, interictal spikes, and spontaneous seizures in cortical and hippocampal networks . One of them, the APdE9 transgenic mouse model, generated by crossing transgenic mice expressing the APP human protein and the human PS1‐dE9 (deletion of exon 9), has been reported to have spontaneous seizures and increased neuronal excitability .…”

Stage‐dependent involvement of ADAM10 and its significance in epileptic seizures

“…25 In addition, increased β-site cleavage products and epileptic seizures were observed in APPSWE mice that were developed to simulate extracellular Aβ aggregation. 26 All of these findings support the notion that ADAM10 could protect against epileptic seizures in AD.…”

Tau Depletion in APP Transgenic Mice Attenuates Task-Related Hyperactivation of the Hippocampus and Differentially Influences Locomotor Activity and Spatial Memory

“…Roberson et al, 2007 ); briefly, J20 mice cross-bred to mice deficient in tau (tau KO) showed levels of hippocampal activity that were similar to those displayed by WT mice. Earlier authors proposed that the hyperexcitability observed in J20 mice results from Aβ -induced Fyn-mediated NMDA receptor activation (Ittner et al, 2010 ; Roberson et al, 2011 ) this interpretation is supported by reports that most APP transgenic mice exhibit spontaneous seizures and/or increased epileptiform EEG activity (Ziyatdinova et al, 2016 ).…”