Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

Macauley, Shannon L.; Stanley, Molly; Caesar, Emily; Yamada, Steven A.; Raichle, Marcus E.; Perez, Ronaldo; Mahan, Thomas E.; Sutphen, Courtney L.; Holtzman, David M.

doi:10.1172/jci79742

Cited by 180 publications

(183 citation statements)

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“…[6][7][8], the regulation of cellular redox states (9,10), the regulation of apoptosis (11), the provision of ATP for membrane pumps (12)(13)(14), and the regulation of cell excitability (15,16). More recently, similar functions of AG have been observed in the posttranscriptional control of T-cell effector function (17,18), an observation now extended to the microglia (19), where it is associated with an activated state related to inflammation as well as synaptic pruning.…”

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confidence: 89%

Brain aerobic glycolysis and motor adaptation learning

Shannon

Vaishnavi

Vlassenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed aerobic glycolysis (AG). Because of the known role of glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learningdependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual-motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task. PET scans before and after task performance indicated a sustained increase in AG in left BA 44 accompanied by decreased oxygen consumption. Intersubject variability in behavioral adaptation rate correlated strongly with changes in AG in this region, as well as functional connectivity, which is consistent with a role for AG in synaptic plasticity.T he resting brain's energy needs are supported almost entirely by the metabolism of glucose to carbon dioxide and water (1). The first step of this process, glycolysis, requires no oxygen whereas the second step, oxidative phosphorylation, does. In the normal adult human brain, 10-15% of the glucose never reaches the second step-it is shunted away from oxidative phosphorylation despite the presence of adequate oxygen (2-5). This process is commonly referred to as aerobic glycolysis (AG).Several roles for AG have been identified, including biosynthesis (for recent reviews, see refs. 6-8), the regulation of cellular redox states (9, 10), the regulation of apoptosis (11), the provision of ATP for membrane pumps (12)(13)(14), and the regulation of cell excitability (15, 16). More recently, similar functions of AG have been observed in the posttranscriptional control of T-cell effector function (17, 18), an observation now extended to the microglia (19), where it is associated with an activated state related to inflammation as well as synaptic pruning.In the developing human brain, at a time when synaptic growth rates are highest (approximately age 10), total glucose consumption is twice that of the adult, and 30% of that glucose consumption is AG (a recent summary of this early literature is contained in ref. 20), suggesting an important role in brain development. Another remarkable feature of AG in the adult human brain is that it varies regionally (21): nearly 25% of resting glucose consumption in the medial prefrontal cortex is AG whereas AG constitutes as little as 2% glucose consumption in the cerebellum and medial temporal lobes. Correlation of these regional data with regional gene expression in the adult human brain revealed increased gene expression typical of infancy (i.e., neotony) that is related to synapse formation and growth (20).Further supporting the link between AG and plasticity are findings demonstrating that lactate, released by astrocytes and taken up by neurons, is critical for memory formation. Neuronal uptake of lactate ch...

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confidence: 89%

Brain aerobic glycolysis and motor adaptation learning

Shannon

Vaishnavi

Vlassenko

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Neurons also produce lactate in pathological conditions. This lactate is involved in the pathogenesis of diverse neurodegenerative diseases (91)(92)(93). Similarly, augmented lactate accumulation has been identified as one of the most important deleterious effects of hyperglycemia (94).…”

Section: Discussionmentioning

confidence: 99%

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

Rahman

Jha

Kim

et al. 2016

Journal of Biological Chemistry

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The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy.Painful neuropathy is one of the most common complications of diabetes. Patients with diabetes frequently exhibit a variety of aberrant sensations, including pain hypersensitivity (1, 2). Interrelation and mutual perpetuation of distinct aberrations of specific metabolic pathways cause painful diabetic neuropathy. Furthermore, painful diabetic neuropathy probably results from a combination of metabolic and immune factors (3, 4). Metabolic aberrations are thought to be early events in painful diabetic neuropathy, leading to biochemical, structural, and functional changes in the dorsal root ganglion (DRG) 3 and its nerve trunk (5, 6). Likewise, hyperglycemia-induced immune activation creates an inflammatory microenvironment surrounding the influenced nerves (7).The DRG is pathologically important in diabetes presenting with painful neuropathic states, which patients with early polyneuropathy commonly experience (8). Ganglionic sensory neurons are devoid of any special protection by the blood-brain or blood-nerve barrier and have higher metabolic requirements than the nerve trunk, which makes the ganglion a vulnerable site in the pathogenesis of diabetic neurop...

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“…In vitro studies demonstrate a common pathogenic mechanism (Sridhar et al 2006;Diamant et al 2006). Whereas brain hyperglycemia mediates hippocampal neuron responses (Macauley et al 2015), BCHE levels also correlate with cerebral glucose metabolism and cerebral Ab load (Darreh-Shori et al 2011). BChE associates particularly with the malignant form of Ab plaques, suggesting its role in transforming non-fibrillar to the malignant fibrillar form (Reid and Darvesh 2015).…”

Section: Potential Role Of Butyrylcholinesterase In Linking Diabetes mentioning

confidence: 99%

“…This has been demonstrated utilizing both neuropsychological instruments and surrogates such as change in MRI volumes (van den Berg et al 2010;van Harten et al 2006;Reijmer et al 2011). Individuals with elevated blood glucose levels are at an increased risk to develop dementia, and those with elevated blood glucose levels have a more pronounced conversion from MCI to AD, suggesting that disrupted glucose homeostasis could play a more causal role in AD pathogenesis (Macauley et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Observational studies have also shown an increase in the incidence of other types of dementia than AD or VaD in DM (Gudala et al 2013;Macauley et al 2015;Irie et al 2008;Ahtiluoto et al 2010). Therefore, the precise mechanisms involved in the development of cognitive impairment in diabetic patients are not yet fully understood (Alafuzoff et al 2009;Feinkohl et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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The diabetic brain and cognition

et al. 2017

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The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders

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Hyperglycemia modulates extracellular amyloid-β concentrations and neuronal activity in vivo

Cited by 180 publications

References 29 publications

Brain aerobic glycolysis and motor adaptation learning

Brain aerobic glycolysis and motor adaptation learning

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy

The diabetic brain and cognition

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