Contribution of early Alzheimer's disease‐related pathophysiology to the development of acquired epilepsy

Abstract

Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticAβ mice whether AD-like pathology renders neuronal networks more susceptible to the development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticAβ mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticAβ mice compared to wild-type littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibres and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble Aβ species by intracerebroventricular Aβ-specific antibody application mitigated the hyperexcitable phenotype of ArcticAβ mice and prevented early SRS onset. Therefore, the development of seizures at early stages of AD is mediated primarily by Aβ species causing widespread changes in synaptic function.

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

“…We evaluated the hippocampal expression of core clock genes and PAR bZIP TFs at different stages during epileptogenesis by injecting KA into the right dorsal hippocampus, a well-established model of TLE 35 . The pathogenesis of this model follows a stereotypic pattern 23,35 , characterized by an initial status epilepticus lasting up to 1 dpi, followed by a silent latent period and the occurrence of spontaneous recurrent seizures in the chronic period starting at about 14 dpi. The expression of clock genes and PAR bZIP TFs was evaluated at two (6 and 14 dpi) or four ZT time-points (1 and 28 dpi) over a day to exclude possible phase shift in clock gene expression amplitude.…”

“…After 14 days of expression, animals were sacrificed, and their brain processed for the gene expression and fluorescent microscopy analyses. Histology and immunohistochemistry were performed as described in our previous work 22,23 . Brain sections were stained with the following antibodies: GFAP (DAKO Schweiz, Z334, 1:20000), Iba-1 (Wako, 019-19741, 1:3000) and NeuN (Chemicon, MAB377, 1:1000).…”

Precuneus-Dominant Degeneration of Parietal Lobe Is at Risk of Epilepsy in Mild Alzheimer's Disease

“…Because of converging paths between epilepsy and AD (24) and the higher mortality of AD patients with seizures (25), we aimed to study the utility of structural brain magnetic resonance imaging in the signaling of seizures in mild phase of AD.…”

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

“…Because our goals are to possibly alter the seizure burden and deficit in spatial learning after epileptogenesis during the chronic phase in IHKA animals, we tested if the seizure burden continues changing over time or if the animals eventually reached a relatively constant seizure phenotype with a steady state in seizure frequency as suggested previously in IHKA rats and mice. [23][24][25][26][27] Although several studies describe the early development of epilepsy in the IHKA mouse model, 23,24,26,27,30,31 few if any have investigated the stability of seizure burden across several months into the chronic period. To test this, we recorded IHKA-treated animals that were implanted after reaching the chronic phase of temporal lobe epilepsy utilizing continuous video-EEG.…”