The intracerebral injection of Aβ1-42 oligomers does not invariably alter seizure susceptibility in mice

Maxime Vande Vyver; Louise Daeninck; Gino De Smet; Najat Aourz; Surajit Sahu; Sebastiaan Engelborghs; Kris Pauwels; Dimitri De Bundel; Ilse Smolders

doi:10.3389/fnagi.2023.1239140

The intracerebral injection of Aβ_1-42 oligomers does not invariably alter seizure susceptibility in mice

Front Aging Neurosci. 2023 Sep 7:15:1239140. doi: 10.3389/fnagi.2023.1239140. eCollection 2023.

Authors

Maxime Vande Vyver^{1

2

3

4}, Louise Daeninck¹, Gino De Smet¹, Najat Aourz¹, Surajit Sahu¹, Sebastiaan Engelborghs^{2

3

4}, Kris Pauwels⁵, Dimitri De Bundel¹, Ilse Smolders¹

Affiliations

¹ Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Research Group Experimental Pharmacology (EFAR), Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
² Department of Neurology and Bru-BRAIN, Universitair Ziekenhuis Brussel, Brussels, Belgium.
³ NEUR Research Group, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium.
⁴ Department of Biomedical Sciences, Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
⁵ RESEARCH Department, Vrije Universiteit Brussel, Brussels, Belgium.

Abstract

Objectives: Epileptiform activity and seizures are present in patients with Alzheimer's disease (AD) and genetic animal models of AD. Amyloid beta 1-42 (Aβ_1-42) oligomers are thought to be crucial in AD and can cause neuronal hyperexcitability in vitro. However, it is unclear whether these Aβ_1-42 oligomers cause the increased seizure susceptibility in vivo in people with AD and in AD animal models, nor via which mechanisms it would do so. We investigated this question by injecting Aβ_1-42 oligomers intracerebrally in mice and assessed its impact on seizure susceptibility.

Materials and methods: We performed a single intracerebral injection of synthetic Aβ_1-42 oligomers or scrambled Aβ_1-42 in NMRI mice in three different cohorts and subjected them to an i.v. infusion of a chemoconvulsant. We evoked the seizures 1.5 h, 1 week, or 3 weeks after the intracerebral injection of Aβ_1-42 oligomers, covering also the timepoints and injection locations that were used by others in similar experimental set-ups.

Results: With a thioflavine T assay and transmission electron microscopy we confirmed that Aβ_1-42 monomers spontaneously aggregated to oligomers. We did not find an effect of Aβ_1-42 oligomers on susceptibility to seizures - evoked 1.5 h, 1 week or 3 weeks - after their intracerebral injection.

Significance: The lack of effect of Aβ_1-42 oligomers on seizure susceptibility in our experiments contrasts with recent findings in similar experimental set-ups. Contradicting conclusions are frequent in experiments with Aβ_1-42 and they are often attributed to subtle differences in the various aggregation forms of the Aβ_1-42 used in different experiments. We confirmed the presence of Aβ_1-42 oligomers with state-of-the-art methods but cannot ascertain that the protein aggregates we used are identical to those used by others. Whether our findings or those previously published best represent the role of Aβ_1-42 oligomers on seizures in AD remains unclear.

Keywords: Alzheimer’s disease; amyloid beta 1-42; epilepsy; oligomer; seizure.