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FUELING THE GLUCOSE-STARVED ALZHEIMER’S BRAIN: CATABOLISM OF WHITE MATTER IN THE BRAIN TO GENERATE KETONE BODIES

      Background

      The brain is the most energetically demanding organ of the body, and is thus vulnerable to even a modest decline in glucose availability and metabolism required to generate ATP. Glucose hypometabolism is an early endophenotype of risk for Alzheimer’s disease (AD) which progressively worsens with disease.

      Methods

      Analyses were conducted in the aging female mouse followed by analyses in brain of gene expression, biochemical analyses and electron microscopy of myelin with AD relevant brain regions.

      Results

      Early during female brain aging the decline in estrogenic control of the bioenergetic system is associated with decline in glucose metabolism and activation of a systems biology adaptive response which involves activation of a starvation response pathway and reliance on ketone bodies as an alternative fuel to generate ATP. Activation of the myelin catabolism pathway was initiated by decline in mitochondrial respiration, increased mitochondrial hydrogen peroxide production and induction of the cytosolic-phospholipase-A2 sphingomyelinase pathway. Electron microscopic and lipidomic analyses confirmed myelin degeneration. An increase in fatty acids and mitochondrial fatty acid metabolism machinery was coincident with a rise in brain ketone bodies and decline in plasma ketone bodies. This mechanistic pathway and its sequentially phased activation, links glucose hypometabolism and mitochondrial dysfunction associated with endocrine aging with later age development of white matter degeneration.

      Conclusions

      The catabolism of myelin lipids to generate ketone bodies can be viewed as a systems level adaptive response to address brain fuel and energy demand. The mechanistic pathway leading to white matter catabolism in the aging female brain provides multiple therapeutic targets to prevent and treat white matter degeneration in AD. Further, the pathways leading to catabolism of white matter in the female brain is likely to be relevant to the aging male brain at risk for AD. Therapeutically targeting stages of disease and associated mechanisms will be critical. Research was supported by NIH National Institute on Aging P01AG026572 and R01AG032236 to RDB.