Trimethylamine <i>N</i>-oxide reduces neurite density and plaque intensity in a murine model of Alzheimer’s disease

ABSTRACT Background Alzheimer’s disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N -oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology. Objective We assessed the direct impact of TMAO on AD progression. Methods To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks. Results Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain, as assessed through quantitative brain microstructure imaging with neurite orientation dispersion and density imaging (NODDI) magnetic resonance imaging (MRI). Amyloid-β plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis of the cortex revealed that TMAO treatment impacted the expression of 31 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-β precursor protein processing. TMAO treatment did not alter astrocyte and microglial response (as determined by histological analysis) nor cortical synaptic protein expression. Conclusion These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density.