Early metabolic changes in the brain of Alzheimer's disease rats are driven by GLAST+ cells.

Glucose metabolic dysfunction is a hallmark of Alzheimer's disease (AD) pathology and is used to diagnose the disease or predict imminent cognitive decline. The main method to measure brain metabolism is positron emission tomography with 2-Deoxy-2-[F]fluoroglucose ([F]FDG-PET). The cellular origin of changes in the [F]FDG-PET signal in AD is controversial. We addressed this by combining [F]FDG-PET with subsequent cell-sorting and γ-counting of [F]FDG-accumulation in sorted cell populations. 7-month-old male TgF344-AD rats and wild-type controls (n = 24/group) received sham or ceftriaxone (200 mg/kg) injection prior to [F]FDG-PET imaging to increase glutamate uptake and glucose utilisation. The same animals were injected again one week later, and radiolabelled brains were dissected, with hippocampi taken for magnetically-activated cell sorting of radioligand-treated tissues (MACS-RTT). Radioactivity in sorted cell populations was measured to quantify cell-specific [F]FDG uptake. Transcriptional analyses of metabolic enzymes/transporters were also performed. metabolism in the frontal association cortex of TgF344-AD rats was identified using [F]FDG-PET, whereas metabolism was identified in the hippocampus using MACS-RTT. Hypermetabolism was primarily driven by GLAST+ cells. This was supported by transcriptional analyses which showed alteration to metabolic apparatus, including upregulation of hexokinase 2 and altered expression of glucose/lactate transporters. See Figure 1 for summary.