Whole-brain mapping of metabolic alterations in a mouse model of Alzheimer's disease by desorption electrospray ionization mass spectrometry imaging

There is growing evidence that metabolic dysregulation contributes to the pathogenesis of Alzheimer's disease (AD). It is however difficult to detect multiple metabolites simultaneously in the different areas of the entire AD brain. Our research used a modified mass spectrometry imaging technique based on desorption electrospray ionization to visualize the spatial distributions of more than 300 compounds, including 119 putative metabolite candidates, in the whole brain slices from AD mice. Through such imaging measurements, we had quantified the level changes of more than 70 metabolites in 12 brain regions of AD mice. We had also evaluated metabolic pathway alterations in AD mice of various ages. In AD mice, we found a dysfunctional glutamine-glutamate/GABA cycle with deficient production and release of glutamate in glutamatergic neurons and aberrant increase of GABA. Disordered metabolism of excitatory glutamate and inhibitory GABA might contribute to the abnormal neural activity. The untargeted mapping of metabolic dysregulations during pathological progression in the AD model might provide implications for the pathogenesis and treatment of AD. • Mass spectrometry imaging allowed simultaneous mapping of over 300 compounds. • The level changes of 71 metabolites were investigated in 12 brain regions in a mouse model of Alzheimer's disease. • About 20 metabolic pathways were examined in the mouse brains of Alzheimer's disease at different ages. • Dysregulated metabolism of neurotransmitters led to impaired neuronal firing in Alzheimer's disease mice.