Abstracts

Rationale: Alzheimer s disease (AD) is associated with a significantly increased risk of seizures. Approximately 7-21% of patients with AD will have at least 1 seizure during the duration of their illness, and the incidence may be as high as 80% in certain familial cases. Recent evidence suggests that neuronal hyperexcitability may contribute to the memory impairments in AD. Transgenic AD mice, harboring a mutated human amyloid precursor protein, were reported to have frequent seizures and epileptiform activity. These animals were further shown to have compensatory inhibitory sprouting in the dentate gyrus of the hippocampus, which could have a significant adverse effect on memory function. Despite these important findings, seizures in animal models of AD have not been fully characterized. Specifically, age-dependent impairments in spatial memory seen in AD mice may not be detectable until 12 months of age, and the severity of seizures at this age is not known. In this study we characterize seizures and epileptiform activity in aged double transgenic AD mice by continuous in vivo video-EEG monitoring. Characterizing EEG abnormalities in both animal models and AD patients is a critical step towards assessing antiepileptic therapy as part of a comprehensive treatment strategy for patients with AD. Methods: 10 double transgenic AD mice (APPswe/PSEN?E9) and WT controls (C57B6) underwent EEG electrode implantation and 3-channel continuous video-EEG monitoring (Pinnacle Systems). The mice were anesthetized, and 6 screw electrodes drilled into the skull. The electrode contacts were attached to a 6-pin connector, and secured using dental acrylic. Each animal underwent a total of at least 48 hours of continuous EEG recordings at ages 8 and 12 months. EEGs were analyzed manually, with the examiner blinded to genotype. Results: The majority of transgenic AD mice showed significant spontaneous EEG abnormalities compared to WT controls. These included multiple convulsive seizures, isolated epileptiform discharges, and brief spike-wave seizures (SWS) with full behavioral arrest. Spike-wave seizures have not previously been described in AD mice. Conclusions: Our results demonstrate that seizures are common in aged double transgenic AD mice. The finding of spike-wave seizures in this mouse model is of particular interest as they could clearly affect cognitive performance, and would be impossible to detect without video-EEG monitoring. Future investigations will be important to elucidate the mechanisms underlying seizures in AD. We have previously shown that cellular prion protein (PrPC) is required for memory impairments and other prominent phenotypes in double transgenic AD mice, and we are now assessing the role of PrPC in mediating the aberrant neuronal hyperexcitability demonstrated in our crrent study. Our data presented here would support prospective long-term EEG monitoring of patients with AD to fully characterize the incidence of seizures in this patient group. This could lead to future studies evaluating the use of effective anticonvulsant therapy as a novel treatment strategy in AD.