Early astrocytic dysfunction is associated to mistuned synapses as well as anxiety and depressive-like behavior in the AppNL-F mouse model of Alzheimers disease

Abstract

Alzheimers disease is the most common neurodegenerative disease, reported as 75 to 80% of dementia cases worldwide. Unfortunately, there are to date no disease modifying treatments available for this mental illness. It is therefore urgent to identify new pharmacological targets. Alzheimers disease is thought to be caused by important phosphorylation of the microtubule associated protein Tau and abnormal amyloid-beta (A beta) accumulation around brain cells, together causing neurodegeneration. Whether the late phases of the disease are well described, recent evidence suggest synaptic impairments at a pre-A beta plaque stage. However, the underlaying mechanisms remain yet to be clarified. In this study we used the AppNL-F knock-in mouse model of Alzheimers disease which carries two disease-causing mutations inserted in the amyloid precursor protein (App) gene and shows pathological A beta plaques not earlier than fifteen months of age. To better understand early changes, we investigated in six months old animals, synaptic plasticity, and its potential pharmacological targeting in the treatment of this pathology. Our electrophysiological recordings revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a higher apathy-like and depression-like behavior. Interestingly, a single injection of ketamine (5mg/kg), twenty-four hours prior to experiment, partially corrected synaptic and depression-like behavior observed in six months old animals, compared to non-treated controls. In contrast with the amyloid-hypothesis of Alzheimers disease, our study shows that earlier synaptic impairments could at least in part be the cause of the later-on observed symptoms, which could be prevented by pharmacological intervention.