EDITOR'S CHOICE IN DISEASE & MEDICINE
L. Wu et al., “Human ApoE isoforms differentially modulate brain glucose and ketone body metabolism: Implications for Alzheimer’s disease risk reduction and early intervention,” J Neurosci, 38:6665–81, 2018.
GOOD GENE, BAD GENE
Humans carry three different isoforms of the ApoE gene, which affects Alzheimer’s risk. Liqin Zhao of the University of Kansas and her colleagues previously found that the gene plays a role in brain metabolism when expressed in mice; in a new study, they looked for the pathways involved.
LEAVING AN IMPRESSION
Zhao’s team engineered female mice to express the human versions of either ApoE2, ApoE3, or ApoE4, and analyzed expression of 43 genes involved in energy metabolism in their cortical tissue.
Mice with ApoE2 showed higher levels of proteins needed for glucose uptake and metabolism in their brains relative to animals harboring the most common isoform in humans, ApoE3. Mice with ApoE4 had lower levels of such proteins. The brain tissue’s glucose transport efficiency also varied across the genotypes, and levels of a key glucose-metabolizing enzyme, hexokinase, were reduced in ApoE4 brains. However, ApoE2 and ApoE4 brains contained similar levels of proteins involved in using ketone bodies, a secondary source of energy, while ApoE3 brains had lower levels of those proteins. “Brain glycolytic function may serve as a significant mechanism underlying the differential impact of ApoE genotypes,” Zhao says.
ApoE4 brains’ reduced ability to extract energy from glucose may contribute to Alzheimer’s pathology by reducing synaptic activity and increasing susceptibility to cellular stress. While ApoE4 increases risk of developing Alzheimer’s, ApoE2 lowers it. “One of the many explanations for Alzheimer’s disease is dysfunctional bioenergetics,” says McLean Hospital’s Kai-Christian Sonntag, who was not involved in this work. The study’s authors suggest that developing therapies that provide more energy to the brain could help keep Alzheimer’s at bay.