2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease.

Title2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2011
AuthorsYao J, Chen S, Mao Z, Cadenas E, Brinton RDiaz
JournalPLoS One
Volume6
Issue7
Paginatione21788
Date Published2011
ISSN1932-6203
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Deoxyglucose, Disease Models, Animal, Energy Metabolism, Female, Ketone Bodies, Mice, Mice, Transgenic, Mitochondria, Nerve Growth Factors, Neurons, Oxidative Stress, Up-Regulation
Abstract

Previously, we demonstrated that mitochondrial bioenergetic deficits preceded Alzheimer's disease (AD) pathology in the female triple-transgenic AD (3xTgAD) mouse model. In parallel, 3xTgAD mice exhibited elevated expression of ketogenic markers, indicating a compensatory mechanism for energy production in brain. This compensatory response to generate an alternative fuel source was temporary and diminished with disease progression. To determine whether this compensatory alternative fuel system could be sustained, we investigated the impact of 2-deoxy-D-glucose (2-DG), a compound known to induce ketogenesis, on bioenergetic function and AD pathology burden in brain. 6-month-old female 3xTgAD mice were fed either a regular diet (AIN-93G) or a diet containing 0.04% 2-DG for 7 weeks. 2-DG diet significantly increased serum ketone body level and brain expression of enzymes required for ketone body metabolism. The 2-DG-induced maintenance of mitochondrial bioenergetics was paralleled by simultaneous reduction in oxidative stress. Further, 2-DG treated mice exhibited a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers, which was paralleled by significantly increased α-secretase and decreased γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway. In addition, 2-DG increased expression of genes involved in Aβ clearance pathways, degradation, sequestering, and transport. Concomitant with increased bioenergetic capacity and reduced β-amyloid burden, 2-DG significantly increased expression of neurotrophic growth factors, BDNF and NGF. Results of these analyses demonstrate that dietary 2-DG treatment increased ketogenesis and ketone metabolism, enhanced mitochondrial bioenergetic capacity, reduced β-amyloid generation and increased mechanisms of β-amyloid clearance. Further, these data link bioenergetic capacity with β-amyloid generation and demonstrate that β-amyloid burden was dynamic and reversible, as 2-DG reduced activation of the amyloidogenic pathway and increased mechanisms of β-amyloid clearance. Collectively, these data provide preclinical evidence for dietary 2-DG as a disease-modifying intervention to delay progression of bioenergetic deficits in brain and associated β-amyloid burden.

DOI10.1371/journal.pone.0021788
Alternate JournalPLoS ONE
PubMed ID21747957
PubMed Central IDPMC3128612
Grant ListP01 AG026572 / AG / NIA NIH HHS / United States
R01 AG032236 / AG / NIA NIH HHS / United States
2R01AG032236 / AG / NIA NIH HHS / United States
5P01AG026572 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D