2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease

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.

Metabolic study of Alzheimer’s disease using mutant C. elegans

“…In contrast, in mammalian systems, both glucose and glycerol induce Aβ toxicity [463,527,528]. Interestingly, we also found that 2DOG administration significantly reduced Aβ-mediated paralysis, which is consistent with results in mammalian cell lines and mouse models [31,32]. Understanding this point of contradiction may provide valuable insight into proteotoxicity resulting from hyperglycemia.…”

“…In our study, MICA was not able to reduce dld-1 gene and protein expression. It has, however, been known to inhibit DLD protein activity and reduce downstream energy metabolism [32,496]. The suppression of dld-1 by RNAi in C. elegans is associated with stress resistance [46,409].…”

“…It is well known that both Aβ and NFTs impair mitochondrial functions [29,30]. Suppression of glucose energy metabolism (oxidative phosphorylation) showed reduction in Aβ toxicity in model systems as well as in neuronal cell lines [31,32] whereas, increase in oxidative phosphorylation was found to enhance the Aβ toxicity [33].…”

“…This is supported by the observation that reduced glucose metabolism and associated enzyme activities were observed in AD patients [41, 433-435, 437, 511]. In contrast, there is a decrease in Aβ-toxicity after caloric restriction or inhibition of glucose catabolism, which indicates that reduction in glucose-associated metabolism protects against neurodegeneration [31,32,45,401,402,438,512]. These contradictory observations mark glucose metabolism as an important target for studies designed to increase our understanding of the progression of AD.…”

“…Exposure to 2-deoxy-d-glucose (2DOG), which is an analogue of glucose that inhibits both glycolysis and oxidative phosphorylation, causes a decrease in Aβ toxicity [31,32].…”