Induced Epileptiform Activity is Increased in Ex Vivo Hippocampal Slices Derived from the AppNL‐F and AppNL‐G‐F Humanised Knock‐In Mouse Models of Alzheimer’s Disease at a Young Age

Abstract

AbstractBackgroundHyperexcitability of neurons in the hippocampus and entorhinal cortex has been demonstrated in Alzheimer’s disease.MethodWe performed multi‐electrode array (MEA) recordings of hippocampal slices from young wild‐type mice, and the AppNL‐F and AppNL‐G‐F knock‐in (App‐KI) mouse models of Alzheimer’s disease amyloidopathy. To investigate the potential for amyloid pathology to drive early hyperexcitability, epileptiform activity was induced in these slices by treatment with aCSF supplemented with high K+ concentrations. A novel automated analysis pipeline was designed to detect epileptiform activity.ResultSubsequent analysis demonstrated an increased frequency of induced epileptiform activity in the hippocampus of App‐KI mice from as early as 4‐5 weeks old — the earliest that hyperexcitability has been observed in these mouse models to date. At this age, amyloid deposition has not yet begun, thus suggesting soluble amyloid oligomers are the driving factor behind increased epileptiform activity. In 12‐13 week‐old AppNL‐ F mice, where amyloid plaque deposition is still yet to occur, increased induced epileptiform activity was maintained, however, slices derived from AppNL‐G‐F mice, which have plaques at this age, had comparable levels of epileptiform activity to WT.ConclusionThese findings suggest that inducible hyperexcitability occurs at an early age in App‐KI mouse models of Alzheimer’s disease amyloidopathy, driven by soluble amyloid oligomers. The paradigm employed — and the robust, comparable metrics which it outputs — are analogous to electroencephalogram recordings and could potentially be used as a clinical biomarker to diagnose Alzheimer’s disease at a pre‐symptomatic, treatment‐sensitive stage.