Hippocampal injections of soluble amyloid-beta oligomers alter electroencephalographic activity during wake and slow-wave sleep in rats.

BACKGROUND: Soluble amyloid-beta oligomers (Aßo) begin to accumulate in the human brain one to two decades before a clinical diagnosis of Alzheimer's disease (AD). The literature supports that soluble Aßo are implicated in synapse and neuronal losses in the brain regions such as the hippocampus. This region importantly contributes to explicit memory, the first type of memory affected in AD. During AD preclinical and prodromal stages, people are also experiencing wake/sleep alterations such as insomnia (e.g., difficulty initiating sleep, decreased sleep duration), excessive daytime sleepiness, and sleep schedule modifications. In addition, changes in electroencephalographic (EEG) activity during wake and sleep have been reported in AD patients and animal models. However, the specific contribution of Aßo to wake/sleep alterations is poorly understood and was investigated in the present study. METHODS: Chronic hippocampal injections of soluble Aßo were conducted in male rats and combined with EEG recording to determine the progressive impact of Aß pathology specifically on wake/sleep architecture and EEG activity. Bilateral injections were conducted for 6 consecutive days, and EEG acquisition was done before, during, and after Aßo injections. Immunohistochemistry was used to assess neuron numbers in the hippocampal dentate gyrus (DG). RESULTS: Aßo injections did not affect the time spent in wakefulness, slow wave sleep (SWS), and paradoxical sleep but altered EEG activity during wake and SWS. More precisely, Aßo increased slow-wave activity (SWA; 0.5-5 Hz) and low-beta activity (16-20 Hz) during wake and decreased theta (5-9 Hz) and alpha (9-12 Hz) activities during SWS. Moreover, the theta activity/SWA ratio during wake and SWS was decreased by Aßo. These effects were significant only after 6 days of Aßo injections and were found with alterations in neuron counts in the DG. CONCLUSIONS: We found multiple modifications of the wake and SWS EEG following Aßo delivery to the hippocampus. These findings expose a specific EEG signature of Aß pathology and can serve the development of non-invasive and cost-effective markers for the early diagnosis of AD or other amyloid-related diseases.

Tau hyperphosphorylation induced by the anesthetic agent ketamine/xylazine involved the calmodulin-dependent protein kinase II.

Tau hyperphosphorylation is a major neuropathological hallmark of many neurodegenerative disorders such as Alzheimer's disease. Several anesthetics have been shown previously to induced marked tau hyperphosphorylation. Although the ketamine/xylazine mixture is one of the most commonly used anesthetic agents in animal research and veterinary practice, the effect of this anesthetic agent on tau phosphorylation still remains to be determined. Here, we found that ketamine-/xylazine-induced a rapid and robust hyperphosphorylation of tau in a dose-dependent manner under normothermic and hypothermic conditions in mice. When used together, ketamine and xylazine exerted a synergistic action on tau phosphorylation most strongly not only on epitopes S396 and S262, but also on other residues (T181, and S202/T205). We observed that activation of the calmodulin-dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation. Since ketamine/xylazine also had a marked impact on other key molecular signaling pathways involving the MAP/microtubule affinity-regulating kinase (MARK), extracellular signal-regulated kinase (ERK), and glycogen synthase kinase-3 (GSK3), our study calls for high caution and careful monitoring when using this anesthetic agent in laboratory animal settings across all fields of biological sciences in order to avoid artifactual results.

Hyperactivity Induced by Soluble Amyloid-ß Oligomers in the Early Stages of Alzheimer's Disease.

Soluble amyloid-beta oligomers (Aßo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aßo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aßo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aßo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.