Amyloid induced neuronal hyperexcitability triggers progressive epilepsy

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AbstractBackgroundUnprovoked seizures are more common in Alzheimer (AD) patients than in general population and subclinical epileptiform activity has been reported in 20‐40% of early‐stage AD patients. Similarly, spontaneous seizures and epileptiform spiking have been reported in all commonly used amyloid plaque producing APP transgenic mouse lines. Furthermore, epileptiform spiking in both AD patients and APP transgenic mice occurs almost exclusive during sleep. These observations speak for common underlying mechanism across species.MethodWith the help of in vivo multichannel and multi‐site local field potential recordings and post‐mortem immunohistochemistry in APP/PS1 mice we have aimed to find answers to three keys questions about AD‐related epilepsy. (1) Is there a focal onset of epileptiform activity in the brain? (2) How does the hyperexcitability relate to amyloid plaque formation? (3) Is the problem primarily of enhanced excitation or attenuate inhibition?ResultIn most cases we have identified hippocampus (both CA1 and dentate gyrus) as the focus for epileptiform activity, although some spikes have cortical origin. Neuronal hyperactivity and epilepsy related sudden deaths tend to peak around the time when first amyloid plaques are formed. On the other hand, intracellular accumulation of full‐length APP or its C‐terminal fragment does not seem to correlate with increased excitability. In line with reported increased glutamate release in the hippocampus of APP/PS1 mice, we found increased vGlut immunopositive terminal around amyloid plaques. Studies on paralbumin‐positive interneurons are ongoing.ConclusionAmyloid plaque formation in the hippocampus is at least one of the triggers for AD‐related epileptiform activity.