Graded perturbations of metabolism in multiple regions of human brain in Alzheimer's disease: Snapshot of a pervasive metabolic disorder

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that displays pathological characteristics including senile plaques and neurofibrillary tangles. Metabolic defects are also present in AD-brain: for example, signs of deficient cerebral glucose uptake may occur decades before onset of cognitive dysfunction and tissue damage. There have been few systematic studies of the metabolite content of AD human brain, possibly due to scarcity of high-quality brain tissue and/or lack of reliable experimental methodologies. Here we sought to: 1) elucidate the molecular basis of metabolic defects in human AD-brain; and 2) identify endogenous metabolites that might guide new approaches for therapeutic intervention, diagnosis or monitoring of AD. Brains were obtained from nine cases with confirmed clinical/neuropathological AD and nine controls matched for age, sex and post-mortem delay. Metabolite levels were measured in post-mortem tissue from seven regions: three that undergo severe neuronal damage (hippocampus, entorhinal cortex and middle-temporal gyrus); three less severely affected (cingulate gyrus, sensory cortex and motor cortex); and one (cerebellum) that is relatively spared. We report a total of 55 metabolites that were altered in at least one AD-brain region, with different regions showing alterations in between 16 and 33 metabolites. Overall, we detected prominent global alterations in metabolites from several pathways involved in glucose clearance/utilization, the urea cycle, and amino-acid metabolism. The finding that potentially toxigenic molecular perturbations are widespread throughout all brain regions including the cerebellum is consistent with a global brain disease process rather than a localized effect of AD on regional brain metabolism.

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…From the standpoint of disease pathophysiology, the higher levels seen in AD participants also match the glucose elevation observed in diabetes mellitus,42 potentially due to their common underpinning of brain insulin resistance 43. Besides these earlier MRS findings, a recent human postmortem study also showed a dramatic glucose elevation in all brain regions of the AD specimens examined 44. Relevant concentrations of glucose in healthy individuals were previously reported as approximately 1 mmol/L in homogenous white matter, 1.1 mmol/L in gray matter,30 and 3.3 mmol/L in CSF 29, 37.…”

Brain Metabolic Changes in Rats following Acoustic Trauma

“…Over the last decade, metabolomics has become one of the major “omics” tools in understanding disease pathology, identifying biomarkers, improving diagnosis and developing personalized therapy (see Botas et al, 2015; Shah et al, 2015 for reviews). In addition, brain metabolomics has been used to understand the pathology and identify potential markers for neurodegenerative diseases in both animal models and human post-mortem tissues due to the fact that metabolic changes in the brain are more likely to reflect disease etiology than those in peripheral biofluids (Pears et al, 2005; Salek et al, 2010; Graham et al, 2013; Fauvelle et al, 2015; Xu et al, 2016). In the present study, 107 small molecules were detected from 12 different brain regions and 88 of them were authentically identified.…”

Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases

“…Based on the symptom profile of these disorders, the accumulation of urea and/or ammonia in the brain could certainly contribute to the neuropathology and symptoms of HD. Interestingly, widespread elevation of urea has also been reported in Alzheimer's disease brain tissue recently (25), suggesting that urea cycle disruption could also be a unifying pathogenic feature of neurodegenerative disease. Not all data are in agreement, however; Green and coworkers (26) identified 3.25-fold lower levels of urea in the postmortem HD striatum in the first 1H-NMR metabolomics study of HD tissue.…”