2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease
Open accessAbstract
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.
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The dosage of 2-DG used in our study (10 mg/kg) was one-two magnitudes less than in prior studies where ketosis was induced.
“Accordingly, to achieve therapeutic benefit, the dosage of 2-DG used in our study (10 mg/kg) was one-two magnitudes less than in prior studies where ketosis was induced.3”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [25]
The Results section reports that a 0.04% 2-DG diet for seven weeks increased serum ketone bodies in female 3xTgAD mice. The paper does not give that dose in mg/kg or establish that the citing study’s 10 mg/kg dose was one to two orders of magnitude lower. No page number is available in our copy. (LLM, conf=0.84)
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Cites
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
Wallace, D. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095751 · Cited by 3,185 · cited 1× · see citing works
“and survival has been well established [1,2,3].”
Intracellular amyloid-β in Alzheimer's disease
LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942 · see citing works
ABAD Directly Links Aß to Mitochondrial Toxicity in Alzheimer's Disease
Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., et al. (2004) · Science · doi:10.1126/science.1091230 · Cited by 1,303 · see citing works
Blalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., & Landfield, P. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308512100 · Cited by 1,025 · cited 1× · see citing works
“decline in glucose-driven ATP generation [14,15].”
Mitochondria take center stage in aging and neurodegeneration
Beal, M. F. (2005) · Annals of Neurology · doi:10.1002/ana.20624 · Cited by 957 · cited 1× · see citing works
“The decline in mitochondrial bioenergetics induces a metabolic crisis that activates a cascade of neurotoxic outcomes, including Ab over-production and increase in oxidative stress, which eventually lead to loss of synaptic functions and neuronal death [34,35].”
BackgroundYao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903563106 · Cited by 940 · cited 6× · see citing works
“Mitochondrial accumulation of Ab has been demonstrated in multiple AD mouse models [7,30].”
BackgroundInfluentialSelf-citationNeuron-glia metabolic coupling and plasticity
Magistretti, P. J. (2006) · Experimental Physiology · doi:10.1113/expphysiol.2010.053157 · Cited by 739 · see citing works
Regional aerobic glycolysis in the human brain
Vaishnavi, S. N., Vlassenko, A. G., Rundle, M. M., Snyder, A. Z., Mintun, M. A., & Raichle, M. E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010459107 · Cited by 738 · cited 1× · see citing works
“Further, these same regions are most vulnerable to development of AD pathology [36,37].”
BackgroundHalagappa, V. K. M., Guo, Z., Pearson, M., Matsuoka, Y., Cutler, R. G., LaFerla, F. M., & Mattson, M. P. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.019 · Cited by 580 · see citing works
Neuron–glia metabolic coupling and plasticity
Magistretti, P. (2006) · Journal of Experimental Biology · doi:10.1242/jeb.02208 · Cited by 576 · cited 1×
“and survival has been well established [1,2,3].”
The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies
Maalouf, M., Rho, J. M., & Mattson, M. P. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.09.002 · Cited by 575 · cited 2× · see citing works
“Caloric restriction has been widely documented to increase expression of stress-response genes, such as Manganese Superoxide Dismutase (MnSOD) and heat shock proteins (HSPs)[50,51], whereas in this study we observed a significant decrease in MnSOD expression and activity and a decrease in Hsp60 expression, via a mecha…”
BackgroundMosconi, L., Mistur, R., Switalski, R., Tsui, W. H., Glodzik, L., Li, Y., Pirraglia, E., De Santi, S., Reisberg, B., Wisniewski, T., et al. (2009) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-008-1039-z · Cited by 487 · cited 1× · see citing works
“Alzheimer’s disease (AD) [1,4,5,6].”
New views of Arc, a master regulator of synaptic plasticity
Shepherd, J. D., & Bear, M. F. (2011) · Nature Neuroscience · doi:10.1038/nn.2708 · Cited by 481 · cited 1× · see citing works
“The clustered distribution of Arc is suggestive of association with the translational machinery within neural processes, which has been observed in multiple models of learning of memory and induced by BNDF [32,33].”
BackgroundNeuroprotective and disease-modifying effects of the ketogenic diet
Gasior, M., Rogawski, M. A., & Hartman, A. L. (2006) · Behavioural Pharmacology · doi:10.1097/00008877-200609000-00009 · Cited by 445 · cited 1× · see citing works
“. Utilization of ketone body-rich diets for multiple neurological conditions has been associated with lower risk of neurodegenerative diseases”
BackgroundMitochondrial free radical production and cell signaling
Cadenas, E. (2004) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2004.02.005 · Cited by 430 · see citing works
Self-citationDuan, W., Guo, Z., Jiang, H., Ware, M., Li, X.-J., & Mattson, M. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0536856100 · Cited by 428 · cited 6× · see citing works
“Further, caloric restriction has been demonstrated to up-regulate expression of neurotrophic factors such as BDNF [46,47,48], which was also achieved by dietary 2DG administration in the current study.”
BackgroundInfluentialLee, J., Duan, W., Long, J. M., Ingram, D. K., & Mattson, M. P. (2000) · Journal of Molecular Neuroscience · doi:10.1385/jmn:15:2:99 · Cited by 407 · cited 6× · see citing works
“Further, caloric restriction has been demonstrated to up-regulate expression of neurotrophic factors such as BDNF [46,47,48], which was also achieved by dietary 2DG administration in the current study.”
BackgroundInfluentialSpatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition
Vlassenko, A. G., Vaishnavi, S. N., Couture, L., Sacco, D., Shannon, B. J., Mach, R. H., Morris, J. C., Raichle, M. E., & Mintun, M. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010461107 · Cited by 404 · see citing works
A Systems Level Analysis of Transcriptional Changes in Alzheimer's Disease and Normal Aging
Miller, J. A., Oldham, M. C., & Geschwind, D. H. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4098-07.2008 · Cited by 385 · cited 1× · see citing works
“decline in glucose-driven ATP generation [14,15].”
The healthy cell bias of estrogen action: mitochondrial bioenergetics and neurological implications
Brinton, R. D. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.07.003 · Cited by 382 · cited 1× · see citing works
“While the normal brain exclusively relies on glucose for energy production [1,25], under long-term starvation or certain disease conditions, the brain can use alternative substrates, such as ketone bodies, for ATP generation [18,20,26].”
BackgroundSelf-citationRamı́rez-Amaya, V., Vazdarjanova, A. I., Mikhael, D. M., Rosi, S., Worley, P. F., & Barnes, C. A. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4342-04.2005 · Cited by 364 · cited 1× · see citing works
“The clustered distribution of Arc is suggestive of association with the translational machinery within neural processes, which has been observed in multiple models of learning of memory and induced by BNDF [32,33].”
BackgroundHippocampal hypometabolism predicts cognitive decline from normal aging
Mosconi, L., De Santi, S., Li, J., Tsui, W. H., Li, Y., Boppana, M., Laska, E., Rusinek, H., & de Leon, M. J. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.12.008 · Cited by 360 · cited 1× · see citing works
“[10,11,12].”
Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models
Patel, N. V., Gordon, M. N., Connor, K. E., Good, R. A., Engelman, R. W., Mason, J., Morgan, D. G., Morgan, T. E., & Finch, C. E. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.09.014 · Cited by 329 · cited 1× · see citing works
“In addition to the bioenergetic benefits of 2-DG, mild weight loss occurred in the mouse group treated with 2-DG, suggesting a potential neurotrophic mechanism of 2-DG via caloric restriction. Caloric restriction has been demonstrated to activate multiple neuroprotective benefits and reduces Aβ pathology in various AD…”
BackgroundCaloric restriction attenuates β‐amyloid neuropathology in a mouse model of Alzheimer's disease
Wang, J., Ho, L., Qin, W., Rocher, A. B., Seror, I., Humala, N., Maniar, K. P., Dolios, G., Wang, R., Hof, P. R., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-3182fje · Cited by 317 · cited 1× · see citing works
“Caloric restriction has been demonstrated to activate multiple neuroprotective benefits and reduces Ab pathology in various AD mouse models [43,44,45].”
BackgroundCerebral ketone body metabolism
Morris, A. A. M. (2004) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-005-5518-0 · Cited by 300 · cited 2× · see citing works
“While the normal brain exclusively relies on glucose for energy production [1,25], under long-term starvation or certain disease conditions, the brain can use alternative substrates, such as ketone bodies, for ATP generation [18,20,26].”
BackgroundWang, J., Ho, L., Zhao, Z., Seror, I., Humala, N., Dickstein, D. L., Thiyagarajan, M., Percival, S. S., Talcott, S. T., & Pasinetti, G. M. (2006) · The FASEB Journal · doi:10.1096/fj.06-6281com · Cited by 299 · cited 1× · see citing works
“Reduction in Ab load has been demonstrated to correlate with improved cognitive function in multiple AD mouse models [39,40,41].”
BackgroundStein, M., Lin, H., Jeyamohan, C., Dvorzhinski, D., Gounder, M., Bray, K., Eddy, S., Goodin, S., White, E., & DiPaola, R. S. (2010) · The Prostate · doi:10.1002/pros.21172 · Cited by 291 · see citing works
Progesterone and Estrogen Regulate Oxidative Metabolism in Brain Mitochondria
Irwin, R. W., Yao, J., Hamilton, R. T., Cadenas, E., Brinton, R. D., & Nilsen, J. (2008) · Endocrinology · doi:10.1210/en.2007-1227 · Cited by 289 · cited 1× · see citing works
“Mitochondrial Preparation Crude brain mitochondria were isolated from the designated hemisphere following our previously established protocol [59] with minor adaptation.”
MethodSelf-citationMitochondria: A therapeutic target in neurodegeneration
Moreira, P. I., Zhu, X., Wang, X., Lee, H., Nunomura, A., Petersen, R. B., Perry, G. L., & Smith, M. A. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.10.007 · Cited by 286 · cited 1× · see citing works
“Alzheimer’s disease (AD) [1,4,5,6].”
Mohanti, B. K., Rath, G. K., Anantha, N., Kannan, V., Das, B. S., Chandramouli, B. A., Banerjee, A. K., Das, S., Jena, A., Ravichandran, R., et al. (1996) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/s0360-3016(96)85017-6 · Cited by 283 · cited 1× · see citing works
“The safety profile of 2-DG has been investigated in multiple preclinical and clinical studies [52,53,54,55,56,57].”
BackgroundABAD enhances Aβ‐induced cell stress via mitochondrial dysfunction
Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J. S., Trillat, A., Stern, D. M., Arancio, O., & Yan, S. S. (2005) · The FASEB Journal · doi:10.1096/fj.04-2582fje · Cited by 254 · cited 1× · see citing works
“model (3xTgAD) [7], and were further exacerbated with AD progression [8,9].”
BackgroundSelf-citationFatty Acid Oxidation and Ketogenesis by Astrocytes in Primary Culture
Auestad, N., Korsak, R. A., Morrow, J. W., & Edmond, J. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb11435.x · Cited by 245 · cited 1× · see citing works
“Further, ketogenic pathways have been demonstrated to exist in astrocytes [20,27].”
BackgroundReddy, P. H., Mańczak, M., Mao, P., Calkins, M. J., Reddy, A. P., & Shirendeb, U. P. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100504 · Cited by 240 · see citing works
Blass, J. P., Sheu, R. K.-F., & Gibson, G. E. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06370.x · Cited by 200 · cited 1× · see citing works
“dehydrogenase (PDH) complex [7,13].”
Dwarakanath, B. S. R., Singh, D., Banerji, A., Sarin, R., Venkataramana, N., Jalali, R., Vishwanath, P., Mohanti, B., Tripathi, R., Kalia, V. K., et al. (2009) · Journal of Cancer Research and Therapeutics · doi:10.4103/0973-1482.55136 · Cited by 195 · cited 1× · see citing works
“The safety profile of 2-DG has been investigated in multiple preclinical and clinical studies [52,53,54,55,56,57].”
BackgroundCorona, C., Frazzini, V., Silvestri, E., Lattanzio, R., Sorda, R. L., Piantelli, M., Canzoniero, L. M. T., Ciavardelli, D., Rizzarelli, E., & Sensi, S. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017971 · Cited by 183 · cited 1× · see citing works
“Reduction in Ab load has been demonstrated to correlate with improved cognitive function in multiple AD mouse models [39,40,41].”
BackgroundDuan, W., Lee, J., Guo, Z., & Mattson, M. P. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:16:1:1 · Cited by 183 · cited 6× · see citing works
“Further, caloric restriction has been demonstrated to up-regulate expression of neurotrophic factors such as BDNF [46,47,48], which was also achieved by dietary 2DG administration in the current study.”
BackgroundInfluentialEffects of caloric restriction on mitochondrial function and gene transcripts in rat muscle
Sreekumar, R., Unnikrishnan, J., Fu, A., Nygren, J., Short, K. R., Schimke, J., Barazzoni, R., & Nair, K. S. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00387.2001 · Cited by 170 · see citing works
A catabolic block does not sufficiently explain how 2-deoxy- d -glucose inhibits cell growth
Ralser, M., Wamelink, M. M. C., Struys, E. A., Joppich, C., Krobitsch, S., Jakobs, C., & Lehrach, H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803090105 · Cited by 166 · cited 1× · see citing works
“Due to the structural similarity between 2-DG and glucose, 2-DG is transported by glucose transporters into the cell where it binds to, but cannot be phosphorylated by, hexokinase thereby disrupting further glycolysis [21].”
BackgroundHypometabolism as a therapeutic target in Alzheimer's disease
Costantini, L. C., Barr, L. J., Vogel, J. L., & Henderson, S. T. (2008) · BMC Neuroscience · doi:10.1186/1471-2202-9-s2-s16 · Cited by 162 · cited 1× · see citing works
“While the normal brain exclusively relies on glucose for energy production [1,25], under long-term starvation or certain disease conditions, the brain can use alternative substrates, such as ketone bodies, for ATP generation [18,20,26].”
BackgroundCharacterizing Alzheimer's disease using a hypometabolic convergence index
Chen, K., Ayutyanont, N., Langbaum, J. B. S., Fleisher, A., Reschke, C., Lee, W., Liu, X., Bandy, D., Alexander, G. E., Thompson, P. M., et al. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.01.049 · Cited by 160 · see citing works
Brinton, R. D. (2008) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2008.06.003 · Cited by 155 · cited 2× · see citing works
“and survival has been well established [1,2,3].”
BackgroundSelf-citationYao, J., Hamilton, R. T., Cadenas, E., & Brinton, R. D. (2010) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2010.06.002 · Cited by 152 · cited 1× · see citing works
“However, this compensatory pathway was temporary and diminished with disease progression [7,17].”
BackgroundSelf-citationKetone body synthesis in the brain: possible neuroprotective effects
Guzmán, M., & Blázquez, C. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2003.05.001 · Cited by 152 · cited 3× · see citing works
“Utilization of ketone body-rich diets for multiple neurological conditions has been associated with lower risk of neurodegenerative diseases [19,20].”
BackgroundReduction of cerebellar glucose metabolism in advanced Alzheimer's disease.
Ishii, K., Sasaki, M., Kitagaki, H., Yamaji, S., Sakamoto, S., Matsuda, K. M., & Mori, E. (1997) · PubMed · Cited by 151 · see citing works
Meilandt, W. J., Cissé, M., Ho, K., Wu, T. Z., Esposito, L., Scearce-Levie, K. A., Cheng, I. H.-J., Yu, G.-Q., & Mucke, L. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2984-08.2009 · Cited by 137 · cited 1× · see citing works
“Reduction in Ab load has been demonstrated to correlate with improved cognitive function in multiple AD mouse models [39,40,41].”
BackgroundChronic ingestion of 2-deoxy-d-glucose induces cardiac vacuolization and increases mortality in rats
Minor, R. K., Smith, D. L., Sossong, A. M., Kaushik, S., Poosala, S., Spangler, E. L., Roth, G. S., Lane, M. A., Allison, D. B., de Cabo, R., et al. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.11.025 · Cited by 133 · cited 1× · see citing works
“While most of the preclinical and clinical studies demonstrated a relative safe profile of 2-DG when used at reasonable doses, long-term chronic administration of high doses of 2-DG, which were 10 or more -fold higher than that used in our study, are associated with adverse effects [58].”
BackgroundYan, S. D., & Stern, D. M. (2005) · International Journal of Experimental Pathology · doi:10.1111/j.0959-9673.2005.00427.x · Cited by 131 · cited 2× · see citing works
“Mitochondrial accumulation of Ab has been demonstrated in multiple AD mouse models [7,30].”
BackgroundAlzheimer's disease: diverse aspects of mitochondrial malfunctioning.
Santos, R. X., Correia, S. C., Wang, X., Perry, G. L., Smith, M. A., Moreira, P. I., & Zhu, X. (2010) · Europe PMC (PubMed Central) · Cited by 120 · see citing works
Soane, L., Kahraman, S., Kristián, T., & Fiskum, G. M. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21498 · Cited by 112 · cited 1× · see citing works
“The decline in mitochondrial bioenergetics induces a metabolic crisis that activates a cascade of neurotoxic outcomes, including Ab over-production and increase in oxidative stress, which eventually lead to loss of synaptic functions and neuronal death [34,35].”
BackgroundThe Neurodegenerative Mitochondriopathies
Swerdlow, R. H. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1095 · Cited by 112 · cited 1× · see citing works
“Mitochondrial bioenergetic deficits have been demonstrated to be closely associated with the pathogenesis of AD [4,7].”
BackgroundAbnormalities of Glucose Metabolism in Alzheimer's Disease
Hoyer, S. (1991) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1991.tb00190.x · Cited by 112 · cited 1× · see citing works
“ratio in healthy elderly controls [16].”
Marsh, J., Mukherjee, P., & Seyfried, T. N. (2008) · Nutrition & Metabolism · doi:10.1186/1743-7075-5-33 · Cited by 92 · cited 1× · see citing works
“The safety profile of 2-DG has been investigated in multiple preclinical and clinical studies [52,53,54,55,56,57].”
BackgroundInhibition of established rat fibrosarcoma growth by the glucose antagonist 2-deoxy-D-glucose.
Kern, K. A., & Norton, J. A. (1987) · PubMed · Cited by 61 · see citing works
Wan, R., Camandola, S., & Mattson, M. P. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00932.2003 · Cited by 41 · see citing works
Preservation of heat stress induced myocardial hsp 72 in aged animals following caloric restriction
Frier, B. C., & Locke, M. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.04.011 · Cited by 15 · cited 1× · see citing works
“Caloric restriction has been widely documented to increase expression of stress-response genes, such as Manganese Superoxide Dismutase (MnSOD) and heat shock proteins (HSPs)[50,51], whereas in this study we observed a significant decrease in MnSOD expression and activity and a decrease in Hsp60 expression, via a mecha…”
BackgroundTurning down tau phosphorylation
Fischer, P. M. (2008) · Nature Chemical Biology · doi:10.1038/nchembio0808-448 · Cited by 11 · cited 2× · see citing works
“The disparity between reduction of Ab pathology and unchanged Tau hyperphosphorylation observed in this study can be bridged by considering that 2-DG could inhibits protein glycosylation [42].”
Background
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Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics
Puchalska, P., & Crawford, P. A. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.12.022 · Cited by 1,617 · see citing works
“…al., 2016; Taegtmeyer, 2016); neurological and neurodegenerative disease (Martin et al., 2016; McNally and Hartman, 2012; Rho, 2017; Rogawski et al., 2016; Yang and Cheng, 2010; Yao et al., 2011); inborn errors of metabolism (Scholl-B€urgi et al, 2015); and exercise performance (Cox et al., 2016).”
BackgroundMitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms
Kerr, J. S., Adriaanse, B. A., Greig, N. H., Mattson, M. P., Cader, M. Z., Bohr, V. A., & Fang, E. F. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.01.002 · Cited by 870 · see citing works
“Treatment of mice with 2-deoxyglucose, which induces mild bioenergetic stress and stimulates ketogenesis, protects neurons against dysfunction and degeneration in a mitochondrial toxin-based model of PD [117] and enhances mitochondrial function and stimulates autophagy and clearance of Aβ [118].”
BackgroundSleiman, S. F., Henry, J., Al-Haddad, R., El Hayek, L., Abou Haidar, E., Stringer, T., Ulja, D., Karuppagounder, S. S., Holson, E. B., Ratan, R. R., et al. (2016) · eLife · doi:10.7554/elife.15092 · Cited by 810 · see citing works
“Similar to our experiments, 2-DG was capable of inducing BDNF in 3xTgAD mice (Yao et al., 2011).”
ResultNormalization of CD4 + T cell metabolism reverses lupus
Yin, Y., Choi, S., Xu, Z., Perry, D. J., Seay, H. R., Croker, B. P., Sobel, E. S., Brusko, T. M., & Morel, L. M. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa0835 · Cited by 611 · see citing works
“Met is commonly used to treat type 2 diabetes, and 2DGhas been tested to treat cancer (41) and Alzheimer’s disease (42).”
The Ketogenic Diet as a Treatment Paradigm for Diverse Neurological Disorders
Stafstrom, C. E., & Rho, J. M. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00059 · Cited by 440 · see citing works
“Transgenic AD mice fed 2DG demonstrated better mitochondrial function, less oxidative stress, and reduced expression of amyloid precursor protein and β-amyloid compared to control animals (Yao et al., 2011).”
BackgroundKetone body metabolism and cardiovascular disease
Cotter, D. G., Schugar, R. C., & Crawford, P. A. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00646.2012 · Cited by 444 · see citing works
Kashiwaya, Y., Bergman, C., Lee, J.-H., Wan, R., King, M. T., Mughal, M. R., Okun, E., Clarke, K., Mattson, M. P., & Veech, R. L. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.11.023 · Cited by 363 · see citing works
“In addition, it was recently reported that dietary supplementation with 2- deoxyglucose increases the level of ketone bodies, enhances mitochondrial function and suppresses Ab pathology in 3xTgAD mice (Yao et al., 2011).”
BackgroundEarly glycolytic reprogramming controls microglial inflammatory activation
Cheng, J., Zhang, R., Xu, Z., Ke, Y., Sun, R., Yang, H., Zhang, X., Zhen, X., & Zheng, L.-T. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02187-y · Cited by 295 · see citing works
The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling
Pathak, D., Shields, L. Y., Mendelsohn, B. A., Haddad, D., Lin, W., Gerencser, A. A., Kim, H., Brand, M. D., Edwards, R. H., & Nakamura, K. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.656405 · Cited by 311 · see citing works
Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update
Cenini, G., & Voos, W. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00902 · Cited by 257 · see citing works
Raefsky, S. M., & Mattson, M. P. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.11.045 · Cited by 274 · see citing works
Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
Cai, Q., & Jeong, Y. Y. (2020) · Cells · doi:10.3390/cells9010150 · Cited by 263 · see citing works
β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology
Shippy, D. C., Wilhelm, C. R., Viharkumar, P. A., Raife, T. J., & Ulland, T. K. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01948-5 · Cited by 257 · see citing works
“improves mitochondrial function, and attenuates Aβ pathology in a mouse model of AD [38].”
BackgroundHu, Y., Mai, W., Chen, L., Cao, K., Zhang, B., Zhang, Z., Liu, Y., Lou, H., Duan, S., & Gao, Z. (2019) · Glia · doi:10.1002/glia.23760 · Cited by 256 · see citing works
Obesity and aging: Molecular mechanisms and therapeutic approaches
Santos, A. L., & Sinha, S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101268 · Cited by 240 · see citing works
Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease
Li, Y., Xia, X., Wang, Y., & Zheng, J. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02613-9 · Cited by 219 · see citing works
“2-deoxy-D-glucose (2-DG), a glucose analog with the 2-hydroxyl group replaced by hydrogen, is a well-known inhibitor of glycolysis since it binds to, but cannot be phosphorylated by, hexokinase [125].”
BackgroundNeth, B., Mintz, A., Whitlow, C. T., Jung, Y., Sai, K., Register, T., Kellar, D., Lockhart, S., Hoscheidt, S., Maldjian, J., et al. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.09.015 · Cited by 191 · see citing works
“In several mouse models of AD, consuming KD decreased brain Aβ content (Kashiwaya et al., 2013; Van der Auwera et al., 2005; Yao et al., 2011), although other studies have reported no impact of KD on Aβ (Beckett et al.”
BackgroundKetone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms
Yang, H.-J., Wei, S., Zhu, F., Wu, J.-P., & Wang, Q. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00585 · Cited by 187 · see citing works
“The accumulation of AGE during healthy aging accelerates the progression of AD.”
BackgroundRothman, S. M., Griffioen, K. J., Wan, R., & Mattson, M. P. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06525.x · Cited by 185 · see citing works
Park, S., Jeon, J., Min, B.-K., Ha, C., Thoudam, T., Park, B.-Y., & Lee, I. (2018) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2018.0101 · Cited by 186 · see citing works
“The stimulated ketogenesis by 2-deoxy-D-glucose treatment lessens both amyloid precursor protein and amyloid-β oligomers by increasing the mitochondrial bioenergetics capacity, leading to the delay progression of Alzheimer’s disease [49].”
Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery
Mosconi, L., Berti, V., Quinn, C. G., McHugh, P. F., Petrongolo, G., Osorio, R. S., Connaughty, C., Pupi, A., Vallabhajosula, S., Isaacson, R., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185926 · Cited by 185 · see citing works
Self-citationMitochondrial Dysfunction: a Potential Therapeutic Target to Treat Alzheimer’s Disease
Nand, S., Singh, C., Singh, A., Singh, M. P., & Singh, S. P. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01945-y · Cited by 213 · see citing works
Klosinski, L. P., Yao, J., Yin, F., Fonteh, A. N., Harrington, M. G., Christensen, T. A., Trushina, E. V., & Brinton, R. D. (2015) · EBioMedicine · doi:10.1016/j.ebiom.2015.11.002 · Cited by 160 · see citing works
“Primary neuron and enriched astrocyte cultures were prepared according to a previously established protocol (Yao et al., 2011a; Gilmore et al., 2007).”
BackgroundMethodInfluentialSelf-citationCalorie restriction mimetics: Can you have your cake and eat it, too?
Ingram, D. K., & Roth, G. S. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.11.005 · Cited by 162 · see citing works
Brownlow, M. L., Benner, L., D’Agostino, D. P., Gordon, M. N., & Morgan, D. (2013) · PLoS ONE · doi:10.1371/journal.pone.0075713 · Cited by 153 · see citing works
DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes
Sýkora, P., Misiak, M., Wang, Y., Ghosh, S., Leandro, G. D. S., Liu, D., Tian, J. Y., Baptiste, B. A., Cong, W., Brenerman, B. M., et al. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1356 · Cited by 136 · see citing works
Shen, Y., Kapfhamer, D., Minnella, A. M., Kim, J.-E., Won, S. J., Chen, Y., Huang, Y., Low, L. H., Massa, S. M., & Swanson, R. A. (2017) · Nature Communications · doi:10.1038/s41467-017-00707-0 · Cited by 133 · see citing works
Neuroketotherapeutics: A modern review of a century-old therapy
Koppel, S. J., & Swerdlow, R. H. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.05.019 · Cited by 140 · see citing works
Yao, J., Rettberg, J. R., Klosinski, L. P., Cadenas, E., & Brinton, R. D. (2011) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.10.005 · Cited by 124 · see citing works
“Results of these analyses demonstrated that dietary 2-DG intake induced ketogenesis, sustained mitochondrial bioenergetics, and reduced pathology in the triple transgenic Alzheimer’s (3xTgAD) mouse model (Yao et al., 2011).”
BackgroundSelf-citationMitochondrial Regulation of Microglial Immunometabolism in Alzheimer’s Disease
Fairley, L. H., Wong, J. H., & Barron, A. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.624538 · Cited by 120 · see citing works
“Transgenic AD mice fed a diet supplemented with 2-DG exhibited increased serum ketone body levels and brain expression of enzymes required for ketone bodymetabolism, as well as decreased oxidative stress and reduced levels of Ab oligomers (111).”
BackgroundNeuroprotection by the Ketogenic Diet: Evidence and Controversies
Gough, S. M., Casella, A., Ortega, K. J., & Hackam, A. S. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.782657 · Cited by 119 · see citing works
Pawlosky, R. J., Kemper, M. F., Kashiwaya, Y., King, M. T., Mattson, M. P., & Veech, R. L. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13958 · Cited by 108 · see citing works
“5), which concurs with previous findings in the same animals of lower Ab accumulation (Kashiwaya et al. 2013) and with previous work in female 3xTgAD mice maintained on a 2-deoxyglucose diet intended to increase blood ketones (Yao et al. 2011).”
BackgroundResultMcPherson, P. A. C., & McEneny, J. (2012) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-011-0112-4 · Cited by 106 · see citing works
“A role for ketone bodies in improving mitochondrial function and reducing systemic oxidative stress has been identified [7], and a state of ketosis has also been shown to be favorable in Alzheimer's disease, ostensibly through a similar mechanism [49].”
Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease
Schugar, R. C., & Crawford, P. A. (2012) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e3283547157 · Cited by 102 · see citing works
Jang, J., Kim, S. R., Lee, J. E., Lee, S.-Y., Son, H. J., Choe, W., Yoon, K., Kim, S. S., Yeo, E., & Kang, I. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010124 · Cited by 107 · see citing works
“A previous study showed that ketogenesis induced by 2-deoxy-D-glucose reduced A β deposition and oxidative stress in the 3xTgAD mouse model [73].”
MethodEstrogen Regulation of Mitochondrial Bioenergetics
Yao, J., & Brinton, R. D. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00010-6 · Cited by 97 · see citing works
“E2 pretreatment protected against inhibitors of mitochondrial electron transport chain in cultured primary neurons (Yao et al., 2011).”
BackgroundSelf-citationMicroglia energy metabolism in metabolic disorder
Kalsbeek, M. J. T., Mulder, L., & Yi, C. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.09.028 · Cited by 93 · see citing works
Ciavardelli, D., Piras, F., Consalvo, A., Rossi, C., Zucchelli, M., Ilio, C. D., Frazzini, V., Caltagirone, C., Spalletta, G., & Sensi, S. L. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.03.005 · Cited by 80 · see citing works
Partial rescue of memory deficits induced by calorie restriction in a mouse model of tau deposition
Brownlow, M. L., Joly‐Amado, A., Azam, S., Elza, M., Selenica, M. B., Pappas, C. A., Small, B. J., Engelman, R. W., Gordon, M. N., & Morgan, D. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.06.001 · Cited by 73 · see citing works
Perspectives of drug-based neuroprotection targeting mitochondria.
Procaccio, V., Bris, C., de la Barca, J. M. C., Oca, F., Chevrollier, A., Amati-Bonneau, P., Bonneau, D., & Reynier, P. (2014) · Revue neurologique (Paris) · doi:10.1016/j.neurol.2014.03.005 · Cited by 71 · see citing works
Sarkar, P., Žaja, I., Bienengraeber, M., Rarick, K. R., Terashvili, M., Canfield, S. G., Falck, J. R., & Harder, D. R. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00001.2013 · Cited by 72 · see citing works
“Substrate unavailability has been proposed to be another mechanism for A -induced downregulation of cellular respiration (1, 55).”
BackgroundThe Emerging Therapeutic Role of NGF in Alzheimer’s Disease
Xu, C., Wang, J., & Jin, W. (2016) · Neurochemical Research · doi:10.1007/s11064-016-1829-9 · Cited by 68 · see citing works
Targeting Mitochondrial Bioenergetics for Alzheimers Prevention and Treatment
Yao, J., & Brinton, R. D. (2011) · Current Pharmaceutical Design · doi:10.2174/138161211798072517 · Cited by 50 · see citing works
Self-citationKumar, A., Karuppagounder, S. S., Chen, Y., Corona, C., Kawaguchi, R., Cheng, Y., Balkaya, M., Sagdullaev, B. T., Wen, Z., Stuart, C., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.013 · Cited by 64 · see citing works
The hormesis principle of neuroplasticity and neuroprotection
Mattson, M. P., & Leak, R. K. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.022 · Cited by 75 · see citing works
Yao, J., Zhao, L.-Q., Mao, Z.-S., Chen, S.-H., Wong, K., To, J., & Brinton, R. (2013) · Brain Research · doi:10.1016/j.brainres.2013.02.021 · Cited by 61 · see citing works
“E2 was included as a positive control as we previously demonstrated that E2 up-regulated mitochondrial respiration both in vitro and in vivo (Yao et al., 2011, 2012).”
MethodSelf-citationAlzheimer's Disease: From Mitochondrial Perturbations to Mitochondrial Medicine
Cardoso, S., Carvalho, C., Correia, S. C., Seiça, R. M. F., & Moreira, P. I. (2016) · Brain Pathology · doi:10.1111/bpa.12402 · Cited by 67 · see citing works
Deoxyglucose prevents neurodegeneration in culture by eliminating microglia
Vilalta, A., & Brown, G. C. (2014) · Journal of Neuroinflammation · doi:10.1186/1742-2094-11-58 · Cited by 58 · see citing works
“of insults, including chemical or electrical induction of epileptic seizures [3,4], a neurotoxin (iminodipropionitrile) [5], brain radiotherapy [6], an inducer of Parkinsonism (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [7] and a triple transgenic model of Alzheimer’s disease [8].”
BackgroundHernández-Zimbrón, L. F., & Rivas-Arancibia, S. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.07.011 · Cited by 54 · see citing works
Ketogenic diets and Alzheimer’s disease
Lange, K. W., Lange, K. M., Makulska-Gertruda, E., Nakamura, Y., Reissmann, A., Kanaya, S., & Hauser, J. (2017) · Food Science and Human Wellness · doi:10.1016/j.fshw.2016.10.003 · Cited by 56 · see citing works
Stafstrom, C. E. (2013) · Epiliepsy currents/Epilepsy currents · doi:10.5698/1535-7597-13.2.103 · Cited by 55 · see citing works
“Other neurologic disorders that may be amenable to ketogenic diet therapy include pain (discussed by Susan Massino) (12), Alzheimer disease (discussed by Marwan Maalouf) (13, 14), amyotrophic lateral sclerosis (discussed by Anne Marie Willis) (15), autism (discussed by Patricia Murphy and Julie Buckley) (16), traumati…”
BackgroundRahman, M. A., Rahman, M. H., Biswas, P., Hossain, M. S., Islam, R., Hannan, M. A., Uddin, M. J., & Rhim, H. (2020) · Antioxidants · doi:10.3390/antiox10010023 · Cited by 70 · see citing works
Brownlow, M. L., Jung, S. H., Moore, R. J., Bechmann, N. A., & Jankord, R. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00129 · Cited by 51 · see citing works
“This is in contrast with compelling evidence of up regulation of BDNF by strategies that, similarly to KD, reduce glycolytic activity such as caloric restriction (Stranahan et al., 2009) and 2-deoxy glucose treatment (Yao et al., 2011).”
ResultSchugar, R. C., Huang, X., Moll, A. R., Brunt, E. M., & Crawford, P. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074806 · Cited by 52 · see citing works
Herrmann, A. G., Deighton, R. F., Bihan, T. L., McCulloch, M. C., Searcy, J. L., Kerr, L. E., & McCulloch, J. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.204 · Cited by 42 · see citing works
2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control
Rho, J. M., Shao, L.-R., & Stafstrom, C. E. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00172 · Cited by 49 · see citing works
Energy restriction and potential energy restriction mimetics
Nikolai, S., Pallauf, K., Huebbe, P., & Rimbach, G. H. (2015) · Nutrition Research Reviews · doi:10.1017/s0954422415000062 · Cited by 43 · see citing works
Peralta, S., Torraco, A., Wenz, T., Garcia, S., Diaz, F., & Moraes, C. T. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt526 · Cited by 42 · see citing works
“Indeed, ketogenic diet slows down the progression of the myopathy of mitochondrial origin in the ‘deletor’ mouse (49) and reduces the pathology in a mouse model of Alzheimer disease by sustained mitochondrial energetic function (50).”
BackgroundSørensen, L. K., Rittig, N. F., Holmquist, E. F., Jørgensen, K. A., Jørgensen, J. O. L., Møller, N., & Johannsen, M. (2013) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2013.08.011 · Cited by 49 · see citing works
“The latter implies that ketone bodies could have an anti-ageing effect, protecting the body against age-related diseases such as Alzheimer's disease, cancer, and cardiovascular disease [3–5].”
BackgroundContribution of astrocytes to metabolic dysfunction in the Alzheimer’s disease brain
Zulfiqar, S., Garg, P., & Nieweg, K. (2019) · Biological Chemistry · doi:10.1515/hsz-2019-0140 · Cited by 45 · see citing works
Alzheimer’s Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α
Sáez-Orellana, F., Octave, J., & Pierrot, N. (2020) · Cells · doi:10.3390/cells9051215 · Cited by 45 · see citing works
“Treatment with the ketone body d-β-hydroxybutyrate protects hippocampal neurons from Aβ toxicity [212] and ketogenic diet decreases brain amyloid pathology in a mouse model of AD [213].”
BackgroundA Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer’s Disease
Pawlosky, R. J., Kashiwaya, Y., King, M. T., & Veech, R. L. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031044 · Cited by 44 · see citing works
“observed an increase in the expression of the ketone-metabolizing enzymes succinyl-CoA:3-ketoacid CoA transferase (SCOT) and acetyl-CoA acetyltransferase 1 (ACAT1) in the same transgenic species maintained on a diet intended to induce mild ketosis [19].”
BackgroundBioenergetic regulation of microglia
Ghosh, S., Castillo, E., Frias, E. S., & Swanson, R. A. (2017) · Glia · doi:10.1002/glia.23271 · Cited by 290 · see citing works
Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics
Ingram, D. K., & Roth, G. S. (2020) · GeroScience · doi:10.1007/s11357-020-00298-7 · Cited by 48 · see citing works
Behavioral, cognitive, and safety profile of 2-deoxy-2-glucose (2DG) in adult rats.
Ockuly, J., Gielissen, J. M., Levenick, C. V., Zeal, C., Groble, K., Munsey, K., Sutula, T., & Stafstrom, C. (2012) · Epilepsy Research · doi:10.1016/j.eplepsyres.2012.04.012 · Cited by 37 · see citing works
Energy and the Alzheimer brain
Mamelak, M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.02.001 · Cited by 46 · see citing works
“Ketogenic diets have been shown to raise brain levels of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) critical for learning, memory and neurogenesis (Yao et al., 2011).”
BackgroundWang, S., Wei, Y.-H., Shieh, D., Lin, L.-L., Cheng, S.-P., Wang, P.-W., & Chuang, J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130959 · Cited by 36 · see citing works
“Positive effects of 2-DG have also been reported in a transgenic model of Alzheimer’s disease [30] and for the treatment of electrically induced epileptic seizure [31].”
BackgroundSchuh, R. A., Jackson, K. C., Schlappal, A. E., Spangenburg, E. E., Ward, C. W., Park, J. H., Dugger, N. V., Shi, G., & Fishman, P. S. (2014) · BMC Neuroscience · doi:10.1186/1471-2202-15-24 · Cited by 36 · see citing works
Lane, R. F., Shineman, D. W., Steele, J., Lee, L. H., & Fillit, H. M. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00007-6 · Cited by 33 · see citing works
Kumar, A., Sharma, M., Su, Y., Singh, S., Hsu, F., Neth, B. J., Register, T. C., Blennow, K., Zetterberg, H., Craft, S., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac262 · Cited by 37 · see citing works
“The 3xTgAD mice treated with a ketone-inducing intervention showed less amyloid and/or tau pathology and improved memory performance.(11,12) Ketones reduce Aβ neurotoxicity by blocking its entry into neurons and decreasing amyloid aggregation, with associated improvement in memory.”
BackgroundDefective Autophagy and Mitophagy in Alzheimer’s Disease: Mechanisms and Translational Implications
Chen, J., He, H., Ye, Q., Feng, F., Wang, W., Gu, Y., Han, R., & Xie, C. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02487-7 · Cited by 36 · see citing works
Unveiling the impact of aging on BBB and Alzheimer's disease: Factors and therapeutic implications
Jha, N. K., Jha, N. K., Nuli, M. V., Gupta, S. K., Kanna, S., Gahtani, R. M., Hani, U., Singh, A. K., Abomughaid, M. M., Abomughayedh, A. M., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102224 · Cited by 42 · see citing works
Makievskaya, C. I., Popkov, V. A., Andrianova, N. V., Liao, X., Zorov, D. B., & Plotnikov, E. Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032576 · Cited by 39 · see citing works
A ketogenic diet differentially affects neuron and astrocyte transcription
Koppel, S. J., Pei, D., Wilkins, H., Weidling, I. W., Wang, X., Menta, B. W., Ortiz, J. P., Kalani, A., Manley, S., Novikova, L., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15313 · Cited by 28 · see citing works
“Doing so could potentially inform a number of studies that find ketone- based interventions variably affect histology and behavioral phenotypes in these models (Aso et al. 2013; Van der Auwera et al. 2005; Beckett et al. 2013; Brownlow et al. 2013; Kashiwaya et al. 2013; Yao et al. 2011).”
BackgroundMetabolic Reprogramming during Microglia Activation
Geric, I., Schoors, S., Claes, C., Gressèns, P., Verderio, C., Verfaillie, C. M., Veldhoven, P. P. V., Carmeliet, P., & Baes, M. I. (2019) · Immunometabolism · doi:10.20900/immunometab20190002 · Cited by 38 · see citing works
“Moreover, several studies have reported beneficial effects of 2-deoxyglucose in Alzheimer’s disease (AD) [34], Parkinson’s disease [35], epilepsy [36] and ischemic stroke [31].”
BackgroundJett, S., Boneu, C., Zarate, C., Carlton, C., Kodancha, V., Nerattini, M., Battista, M., Pahlajani, S. S., Williams, S., Dyke, J. P., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1183228 · Cited by 27 · see citing works
Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease
Shippy, D. C., Evered, A. H., & Ulland, T. K. (2024) · Immunological Reviews · doi:10.1111/imr.13365 · Cited by 29 · see citing works
Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats
Vizuete, A. F. K., de Souza, D. F., Guerra, M. C., Batassini, C., Dutra, M. F., Bernardi, C. L., Costa, A. P., & Gonçalves, C. (2013) · Life Sciences · doi:10.1016/j.lfs.2013.03.004 · Cited by 28 · see citing works
Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice
Blanco-Gandía, M. C., Ródenas-González, F., Pascual, M., Reguilón, M. D., Guerri, C., Miñarro, J., & Rodríguez‐Arias, M. (2021) · Nutrients · doi:10.3390/nu13072167 · Cited by 32 · see citing works
Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer's Mouse Model
Wang, T., Yao, J., Chen, S., Mao, Z., & Brinton, R. D. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00793-6 · Cited by 28 · see citing works
Self-citationDutta, S., Rutkai, I., Katakam, P. V. G., & Busija, D. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13181 · Cited by 27
Moshkin, M. P., Akulov, A., Petrovski, D., Saik, O., Petrovskiy, E. D., Savelov, A. A., & Koptyug, I. (2014) · NMR in Biomedicine · doi:10.1002/nbm.3074 · Cited by 27
Mitochondrial mechanisms in Alzheimer’s disease: Quest for therapeutics
Kalani, K., Chaturvedi, P., Chaturvedi, P., Verma, V. K., Lal, N., Awasthi, S. K., & Kalani, A. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103547 · Cited by 28 · see citing works
ROCK2 inhibition: A futuristic approach for the management of Alzheimer’s disease
Mani, S., Jindal, D., Chopra, H., Jha, S. K., Singh, S. K., Ashraf, G. M., Kamal, M., Iqbal, D., Chellappan, D. K., Dey, A., et al. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104871 · Cited by 28 · see citing works
Jett, S., Dyke, J. P., Andy, C., Schelbaum, E., Jang, G., Boneu, C., Pahlajani, S. S., Diaz, I., Brinton, R. D., & Mosconi, L. (2022) · Scientific Reports · doi:10.1038/s41598-022-26573-5 · Cited by 29 · see citing works
Self-citationBrose, R. D., Lehrmann, E., Zhang, Y., Reeves, R. H., Smith, K. D., & Mattson, M. P. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.08.021 · Cited by 26 · see citing works
“Treatment of 3xTg AD mice with 2-deoxyglucose, which induces mild metabolic stress, bolstered mitochondrial function and reduced Aβ neuropathology (Yao et al., 2011).”
BackgroundBACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid
Findlay, J. A., Hamilton, D. L., & Ashford, M. L. J. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00382 · Cited by 22 · see citing works
“…glucose metabolism has been postulated to result from impaired mitochondrial functioning (Lustbader et al., 2004; Beal, 2005; Bubber et al., 2005), with similar changes observed in a variety of transgenic mouse models of AD (von Kienlin et al., 2005; Yao et al., 2009, 2011; Nilsen et al., 2014).”
BackgroundGlycolytic inhibition: A novel approach toward controlling neuronal excitability and seizures
Shao, L., Rho, J. M., & Stafstrom, C. E. (2018) · Epilepsia Open · doi:10.1002/epi4.12251 · Cited by 29 · see citing works
Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer's disease
Pradeepkiran, J. A., Islam, M. A., Sehar, U., Reddy, A. P., Vijayan, M., & Reddy, P. H. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102734 · Cited by 21 · see citing works
Oliveira, T. P. D., Morais, A. L. B., dos Reis, P. L. B., Palotás, A., & Vieira, L. B. (2023) · Metabolites · doi:10.3390/metabo14010025 · Cited by 22 · see citing works
“KD treatment may lead to neuroprotective effects by reducing A β damage to mitochondria, increasing ATP production, and reducing oxidative stress and glutamate toxicity [120].”
BackgroundInfluentialAging and Aging-Related Diseases: Mechanisms and Interventions
Wang, Z. (2018) · Advances in Experimental Medicine and Biology · doi:10.1007/978-981-13-1117-8 · Cited by 21 · see citing works
Mitochondrial defects: An emerging theranostic avenue towards Alzheimer's associated dysregulations
Mani, S., Swargiary, G., Singh, M., Agarwal, S., Dey, A., Ojha, S. K., & Jha, N. K. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119985 · Cited by 23 · see citing works
Fowler, K. D., Funt, J. M., Artyomov, M. N., Zeskind, B. J., Kolitz, S. E., & Towfic, F. (2015) · Scientific Reports · doi:10.1038/srep14324 · Cited by 20 · see citing works
Mitochondria and Alzheimer's disease
Piaceri, I., Rinnoci, V., Bagnoli, S., Failli, Y., & Sorbi, S. (2012) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.05.033 · Cited by 40 · see citing works
“Very recently it has been shown that deoxyglucose treatment induces ketogenesis, sustains mitochondrial function and reduces pathological changes in the brain of an ADmouse model [55].”
BackgroundMassetti, N., Russo, M., Franciotti, R., Nardini, D., Mandolini, G. M., Granzotto, A., Bomba, M., Pizzi, S. D., Mosca, A., Scherer, R., et al. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210573 · Cited by 25 · see citing works
A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease
Li, W., Kui, L., Tsirukis, D. I., Gong, X., & Tang, M. (2020) · Aging and Disease · doi:10.14336/ad.2020.0105 · Cited by 20 · see citing works
“stress; enhance mitochondrial function; stimulate autophagy and clearance of Aβ [142-149]”
BackgroundSaraswat, K., Kumar, R., & Rizvi, S. I. (2018) · Rejuvenation Research · doi:10.1089/rej.2018.2125 · Cited by 22 · see citing works
“11 In Caenorhabditis elegans , 2-DG has been found to increase mean and maximum life span.”
5‐Methoxyindole‐2‐carboxylic acid (MICA) suppresses A&bgr;‐mediated pathology in C. elegans
Ahmad, W., & Ebert, P. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.04.021 · Cited by 19 · see citing works
Diabesity and Brain Energy Metabolism: The Case of Alzheimer’s Disease
Cardoso, S., Seiça, R. M. F., & Moreira, P. I. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-63260-5_5 · Cited by 22 · see citing works
Wei, L., Wang, R., Wazir, J., Lin, K., Song, S.-Y., Li, L., Pu, W., Zhao, C., Wang, Y., Su, Z.-L., et al. (2022) · Cells · doi:10.3390/cells11192987 · Cited by 18 · see citing works
“A previous study indicated that ketone bodies can serve as auxiliary and alternative fuels during a biochemical crisis [43].”
Background
- Authors
- Yao, J., Chen, S., Mao, Z., Cadenas, E., & Brinton, R. D.
- Affiliations
- University of Southern California (US)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-07-01
- Volume
- 6
- Issue
- 7
- Pages
- e21788
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3128612
- OpenAlex
- W2128876324
- Cited by
- 169
- References
- 60
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 14 · 2022: 14 · 2021: 19 · 2020: 10 · 2019: 13 · 2018: 8 · 2017: 15 · 2016: 11 · 2015: 12 · 2014: 9 · 2013: 13 · 2012: 12
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (R01AG032236, P01AG026572)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- 2-deoxyglucose, ketogenesis, Alzheimer's disease, mitochondrial bioenergetics, ketone body metabolism, amyloid-beta, non-amyloidogenic pathway, APP processing, oxidative stress, brain-derived neurotrophic factor, nerve growth factor, neurotrophic factors, dietary intervention, 3xTg-AD mice, female mice, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Animals, Brain, Deoxyglucose, Disease Models, Animal, Energy Metabolism, Female, Ketone Bodies, Mice, Transgenic, Mitochondria, Nerve Growth Factors, Neurons, Up-Regulation, Amyloid beta-Peptides, Oxidative Stress, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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