Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe ×PS1Δe9 transgenic mouse model of Alzheimer's disease.

Abstract

There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD), however its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, a need exists to find new ways of investigating neuroinflammation in both health and disease. Here we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APP_swe ×PS1_Δe9 transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [¹⁸ F]DPA-714 positron emission tomography and myo-inositol levels using ¹ H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N-acetylaspartate (NAA), choline containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12m-old in the TG mice as assessed by working memory tests. A significant increase in [¹⁸ F]DPA-714 uptake was seen in the hippocampus and cortex of 18m-old TG mice when compared to age matched WT mice and 6m-old TG mice. No overall effect of gene was seen on metabolite levels; however a significant reduction in NAA was observed in 18m-old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in aging.