What's so exciting about Alzheimer's disease? The effect of amyloid ß and tau on seizure susceptibility

Onderzoeksoutput: PhD Thesis


Alzheimer’s disease is the most dreaded disease by people over 60 years of age. This neurodegenerative disorder is the most frequent cause of dementia and results in progressive cognitve impairment consisting predominantly of memory loss in most patients, but can also compromise spatial orientation, language, and behavior. The disease progresses slowly over years, inevitably resulting in profound dementia. To date, no cure exists and the patient’s and physician’s options to slow down the disease are very limited. Deposition of two proteins in the brain is required for a diagnosis of Alzheimer’s disease: amyloid β (Aβ) plaques and tau neurofibrillary tangles. Accumulation of these proteins starts decades before clinical symptoms become apparent. In addition to the cognitive symptoms, people with Alzheimer’s disease more frequently have epilepsy, seizures, and neuronal hyperactivity. There is mounting evidence that the presence of this hyperexcitable phenotype is already present early in the disease and might aggravate the clinical syndrome or even be a driver of the disease.
Aβ is the main constituent of Aβ plaques. It is a breakdown product of amyloid
precursor protein (APP) and many APP transgenic mouse models are more susceptible to seizures or even have epilepsy. However, it is unclear whether Aβ, APP, or other APP breakdown products cause this seizure-prone phenotype. The effect of tau, the second protein involved in Alzheimer’s disease, on brain hyperexcitability is even more subject to debate. Depending on the experimental tau model and the readout used for brain hyperexcitability, completely contradicting results are reported on its effect on neuronal hyperexcitability. Both in vitro and in vivo, the results range from tau promoting hyperexcitability to tau resulting in hypoexcitability, even dominating the effect of APP and Aβ.
If brain hyperexcitability aggravates the clinical syndrome or would contribute to the pathology of Alzheimer’s disease, then preventing or treating this could be an interesting therapeutic approach for Alzheimer’s disease. Understanding how the APP and tau cascade affect the phenotype of a hyperexcitable brain and what their interaction is, is thus a burning question in Alzheimer’s disease research. Over the course of this doctoral thesis, I aim to further dissect the roles of Aβ and tau on brain hyperexcitability.
In the experiments described in Chapter 3, we assessed the effect of tau reduction in primary rat neuronal cultures. Neurons were dissected from the brains of embryonic day 18 wildtype rats and cultured in vitro. With a small interfering ribonucleic acid specific for microtubule-associated protein tau (MAPT) we inhibited the translation of MAPT, the gene encoding for tau, from day in vitro 7 and lowered tau levels by about half in these cultures. We used changes in neuronal calcium concentration as a well-established proxy of neuronal activity. By transducing neurons with a genetically encoded calcium indicator we were able to track neuronal calcium concentration, and thus neuronal activity, in real-time. Our results show that tau reduction drastically lowers neuronal activity in vitro, without affecting neuronal survival. This adds to the body of evidence that tau reduction lowers neuronal activity and is well-tolerated by neurons.
Chapter 4 encompasses our experiments that investigated the effect of Aβ1-42 oligomers on seizure susceptibility in mice. We allowed Aβ1-42 monomers to aggregate spontaneously with a standardized protocol and confirmed the presence of Aβ1-42 oligomers via a biophysical and an imaging method. We then injected these Aβ1-42 oligomers directly into the mice’s ventricles or the dentate gyrus of the hippocampus, one of the key brain regions involved in memory and neuronal hyperactivity in people with Alzheimer’s disease. These mice were then subjected to a provoked seizure induced by different chemoconvulsants: kainic acid, pentylenetetrazole, or 4-aminopyridine. When compared to scrambled Aβ1-42, the intracerebral injection of Aβ1-42 oligomers did not affect seizure susceptibility 90 minutes, 1 week, or 3 weeks after injection. Whether the presence of Aβ1-42 needs to be more widespread, other Aβ peptide lengths or aggregation forms should be used, or different APP metabolites play a key role in seizure susceptibility remains to be investigated.
In Chapter 5, I discuss the experiments in which we investigated the effect of genetic mutations on seizure susceptibility and seizure development in mice. We used mice with mutations affecting the homeostasis of APP, or with mutations affecting both APP and MAPT. The APP/PS1 model has mutations in APP and presenilin 1, and the 3xTg model has mutations in APP, presenilin 1, and MAPT. We subjected these mice to the 6 Hz corneal kindling model, in which repetitive identical electrical currents lead to progressively worsening seizures over time. Both the APP/PS1 and the 3xTg mice had more severe seizures compared with their respective controls. We also tested three clinically approved antiseizure drugs (levetiracetam, brivaracetam and lamotrigine) and found that the seizures in the Alzheimer’s disease mouse models were less reduced by the tested antiseizure drugs.
Our results strengthen the claim that tau reduction inhibits neuronal activity. The lack of effect of an intracerebral injection of Aβ1-42 oligomers at different timepoints questions the role of local Aβ1-42 oligomers in the increased susceptibility to seizures in Alzheimer’s disease. However, we confirmed that mutations in APP and presenilin 1 that cause autosomal dominant Alzheimer’s disease in people result in increased seizure susceptibility. When we combined mutations in APP, presenilin 1, and MAPT to model accumulation of Aβ and tau in mice as is present in people with Alzheimer’s disease, seizure susceptibility was also increased.
Originele taal-2English
Toekennende instantie
  • Vrije Universiteit Brussel
  • University of Antwerp
  • Smolders, Ilse, Promotor
  • Engelborghs, Sebastiaan, Promotor
  • De Bundel, Dimitri, Co-Promotor
  • Nagels, Guy, Co-Promotor
Datum van toekenning12 sep 2023
StatusPublished - 12 sep 2023


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