Brain Arginine Metabolism in Early‐onset Alzheimer’s Disease and Frontotemporal Dementia

Abstract

AbstractBackgroundThe semi‐essential amino acid L‐arginine is metabolically versatile with a number of bioactive metabolites that are involved in synaptic plasticity, learning and memory, cerebral blood flow and microtubule stabilization processes. Altered brain arginine metabolism is evident in patients with late‐onset Alzheimer’s disease and has been implicated in the disease pathogenesis. However, the brain arginine metabolic profile is yet to be investigated in early‐onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD).MethodUsing high performance liquid chromatography and liquid chromatography/mass spectrometry, we measured the concentrations of L‐arginine and its downstream metabolites L‐citrulline, L‐ornithine, agmatine, glutamate, glutamine, GABA, putrescine, spermidine and spermine in the hippocampus and frontal and temporal cortices from EOAD (n = 27‐28/region), FTD (n = 27‐31/region) and control (n = 9‐17/region) cases.ResultThere were significantly reduced levels of L‐ornithine in all three brain regions in both groups of dementia cases compared to the controls. Furthermore, the putrescine levels were significantly reduced in all brain regions examined in the FTD cases, and in the temporal cortex and hippocampus of the EOAD cases. In the hippocampus, there were increased L‐arginine levels, but decreased agmatine levels, in both the EOAD and FTD cases relative to the controls.ConclusionThis study demonstrates for the first time that brain arginine metabolism is altered similarly in both EOAD and FTD cases, and therefore suggests that altered L‐arginine metabolism may be a common mechanism involved in the neurodegenerative processes in these two early‐onset dementias. Further research is required to investigate the mechanisms for these metabolite changes and to explore the therapeutic potential of targeting L‐arginine metabolism in EOAD and FTD.