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Intracellular amyloid accumulation may lead to neuronal hyperactivity and epileptiform spiking in transgenic APP/Ps1 and 5xFAD mouse models of Alzheimer’s disease

Year: 2022
Type: dissertation
Abstract: Alzheimer's disease (AD) is associated with increased incidence of epileptiform discharges.The most predominant hypothesis behind AD related epileptiform activity is either accumulation of intracellular soluble Aβ species or formation of extracellular amyloid plaques.In this explorative study development of neuronal hyperactivity was assessed across several age points and brain regions in common 5xFAD and APP/Ps1 mouse models of AD by using dFosB, an immunohistochemical marker of long-term neuronal activity.In addition, the effects of intra-and extracellular Aβ accumulation on neuronal excitability was investigated.Brain slices from wt and transgenic mice at age points of 4, 8 and 12 weeks and 10 months (5xFAD) and 6 and 12 weeks (APP/Ps1) were immunohistochemically double stained with anti-dFosB and anti-W02 antibodies.It was found that hippocampus and neocortex are feasible regions for further investigation at the age of 12 weeks.In addition, dFosB exhibited spiking intensities in the dentate gyrus and entorhinal cortex, whilst the number of dFosB positive cells was higher in the entorhinal cortex and visual-auditory cortex of 5xFAD transgenic mice and in the dentate gyrus of APP/Ps1 transgenic mice at 12 weeks.Interestingly it was for the first time seen, that dFosB signal may locate within the same cells with W02 signal, indicating the possible relation of intracellular Aβ with neuronal activity.In APP/Ps1 transgenic mice high ratios of double-positive cells was found in the entorhinal cortex, as well as in the visual-auditory cortex, retrosplenial cortex, and CA1.Understanding of the mechanisms connecting AD and epilepsy is crucial to develop novel therapeutic strategies to prevent epilepsy-induced worsening of AD-pathology.
Language: English
Open Access status: green
OpenAlex ID: W7215509119
Cites: 2
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Related to: 10