Ketones block amyloid entry and improve cognition in an Alzheimer's model

Yin, Jun; Maalouf, Marwan; Han, Pengcheng; Zhao, Minglei; Gao, Ming; Turner, Dharshaun; Ryan, Christopher M.; Whitelegge, Julian P.; Wu, Jie; Eisenberg, David; Reiman, Eric M.; Schweizer, Felix E.; Shi, Jiong

doi:10.1016/j.neurobiolaging.2015.11.018

Cited by 114 publications

(99 citation statements)

References 60 publications

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“…Similarly, in a multicenter clinical trial with AC-1202 treatment, a drug that increases plasma BHB levels, improvement in Alzheimer's disease assessment scale (ADAS) cognitive scores was observed [58]. Further elevated plasma and brain ketone body levels could also affect AD via a variety of other mechanisms including (1) the blockade of A β 1–42 (the toxic form of β -amyloid) entry into neurons which can decrease oxidative stress and amyloid burden [59] and (2) neuroprotection against β -amyloid toxicity possibly by decreasing ROS production and decreasing BACE1 expression, the rate-limiting enzyme in A β 1–42 production [60]. These beneficial effects of BHB on AD pathogenesis and cognitive decline are intriguing given our data demonstrating a decreased capacity of the periphery to produce/provide KBs following a brief fast in the 3xTg-AD mouse model.…”

Section: Discussionmentioning

confidence: 99%

Differential Fasting Plasma Glucose and Ketone Body Levels in GHRKO versus 3xTg-AD Mice: A Potential Contributor to Aging-Related Cognitive Status?

Griffith

Macklin

Bartke

et al. 2017

International Journal of Endocrinology

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Cognitive function declines with age and appears to correlate with decreased cerebral metabolic rate (CMR). Caloric restriction, an antiaging manipulation that extends life-span and can preserve cognitive function, is associated with decreased glucose uptake, decreased lactate levels, and increased ketone body (KB) levels in the brain. Since the majority of brain nutrients come from the periphery, this study examined whether the capacity to regulate peripheral glucose levels and KB production differs in animals with successful cognitive aging (growth hormone receptor knockouts, GHRKOs) versus unsuccessful cognitive aging (the 3xTg-AD mouse model of Alzheimer's disease). Animals were fasted for 5 hours with their plasma glucose and KB levels subsequently measured. Intriguingly, in GHRKO mice, compared to those in controls, fasting plasma glucose levels were significantly decreased while their KB levels were significantly increased. Conversely, 3xTg-AD mice, compared to controls, exhibited significantly elevated plasma glucose levels and significantly reduced plasma KB levels. Taken together, these results suggest that the capacity to provide the brain with KBs versus glucose throughout an animal's life could somehow help preserve cognitive function with age, potentially through minimizing overall brain exposure to reactive oxygen species and advanced glycation end products and improving mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

Differential Fasting Plasma Glucose and Ketone Body Levels in GHRKO versus 3xTg-AD Mice: A Potential Contributor to Aging-Related Cognitive Status?

Griffith

Macklin

Bartke

et al. 2017

International Journal of Endocrinology

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“…Ketogenic diet, ketone esters (also see Therapeutic use of ketogenic diet and exogenous ketone bodies ), or βOHB administration exert neuroprotection in models of ischemic stroke (Rahman et al, 2014); Parkinson’s disease (Tieu et al, 2003); central nervous system oxygen toxicity seizure (D'Agostino et al, 2013); epileptic spasms (Yum et al, 2015); mitochondrial encephalomyopathy, lactic acidosis and stroke-like (MELAS) episodes syndrome (Frey et al, 2016) and Alzheimer’s disease (Cunnane and Crawford, 2003; Yin et al, 2016). Conversely, a recent report demonstrated histopathological evidence of neurodegenerative progression by a ketogenic diet in a transgenic mouse model of abnormal mitochondrial DNA repair, despite increases in mitochondrial biogenesis and antioxidant signatures (Lauritzen et al, 2016).…”

Section: Ketone Bodies Oxidative Stress and Neuroprotectionmentioning

confidence: 99%

“…Taken together, most reports link βOHB to attenuation of oxidative stress, as its administration inhibits ROS/superoxide production, prevents lipid peroxidation and protein oxidation, increases antioxidant protein levels, and improves mitochondrial respiration and ATP production (Abdelmegeed et al, 2004; Haces et al, 2008; Jain et al, 1998; Jain et al, 2002; Kanikarla-Marie and Jain, 2015; Maalouf et al, 2007; Maalouf and Rho, 2008; Marosi et al, 2016; Tieu et al, 2003; Yin et al, 2016; Ziegler et al, 2003). While AcAc has been more directly correlated than βOHB with the induction of oxidative stress, these effects are not always easily dissected from prospective pro-inflammatory responses (Jain et al, 2002; Kanikarla-Marie and Jain, 2015; Kanikarla-Marie and Jain, 2016).…”

Section: Ketone Bodies Oxidative Stress and Neuroprotectionmentioning

confidence: 99%

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

2017

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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states, and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, recent observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.

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“…A study by Yin et al (2016) showed that APP mice fed ketones had improved memory in Morris water maze and novel object recognition tests and had improved mitochondrial function through restoration of mitochondrial complex I activity and reducing Aβ-42 levels [172]. A ketogenic diet also improved cognitive function in patients with AD [173].…”

Section: Roles For Mitochondria In Bioenergetic Challenge-induced Neumentioning

confidence: 99%

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Raefsky

Mattson

2017

Free Radical Biology and Medicine

193

123

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An important concept in neurobiology is “neurons that fire together, wire together” which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic ‘switch’ in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging.

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Ketones block amyloid entry and improve cognition in an Alzheimer's model

Cited by 114 publications

References 60 publications

Differential Fasting Plasma Glucose and Ketone Body Levels in GHRKO versus 3xTg-AD Mice: A Potential Contributor to Aging-Related Cognitive Status?

Differential Fasting Plasma Glucose and Ketone Body Levels in GHRKO versus 3xTg-AD Mice: A Potential Contributor to Aging-Related Cognitive Status?

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

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