Middle-aged dogs with low and high Aβ CSF concentrations show differences in energy and stress related metabolic profiles in CSF

Background: Amyloid beta (Aβ) accumulation in the brain is one of the earliest findings in Alzheimer's disease (AD). The dog is a natural animal model for amyloid processing and early brain amyloid pathology. The goal of this study is to examine which differences in metabolomic profiles in cerebrospinal fluid (CSF) could be detected in dogs with a difference in CSF Aβ concentrations before amyloid accumulation occurs. Method: Metabolic profiling was performed on CSF from 4 to 8 year old dogs with different CSF Aβ concentrations. Results: Metabolomic profiling of CSF showed differences in brain energy metabolism. More specifically, increases in N-acetylation of amino acids and amino sugars, creatine and pentose metabolism, and a decrease in tricarboxylic acid (TCA) cycle were seen in dogs with a high CSF Aβ concentration. In addition, signs of elevated oxidative stress, higher methionine, lipid and nucleotide metabolism and increased levels of cysteine, myo-inositol and trimethylamine N-oxide were noted in these animals. Conclusions: Differences in energy metabolism and stress mediated metabolic changes are seen in the brain of dogs with different CSF Aβ concentrations, before any amyloid deposition occurs. Similar metabolic changes, as in the high Aβ dogs, have been described in AD in humans and/or transgenic AD mice, some of them in very early phases. General significance: The differences observed in metabolomic profiles could help in identifying potential biomarkers for an increased risk of developing amyloid pathology in the brain and open the door to the evaluation of preventive treatments for amyloid pathology in humans.