Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.

TitleEarly decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.
Publication TypeJournal Article
Year of Publication2013
AuthorsDing F, Yao J, Rettberg JR, Chen S, Brinton RDiaz
JournalPLoS One
Volume8
Issue11
Paginatione79977
Date Published2013
ISSN1932-6203
KeywordsAdaptation, Physiological, Aging, Alzheimer Disease, Animals, Astrocytes, Biological Transport, Active, Blood-Brain Barrier, Disease Models, Animal, Energy Metabolism, Female, Gene Expression, Glucose, Glucose Transporter Type 1, Hexokinase, Hippocampus, Humans, Ketone Bodies, Ketone Oxidoreductases, Lactic Acid, Mice, Mice, Transgenic, Mitochondria, Monocarboxylic Acid Transporters, Neurons
Abstract

We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.

DOI10.1371/journal.pone.0079977
Alternate JournalPLoS ONE
PubMed ID24244584
PubMed Central IDPMC3823655
Grant ListTL1 TR000132 / TR / NCATS NIH HHS / United States
P01AG026572 / AG / NIA NIH HHS / United States
R01AG032236 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D