Publications by authors named "Grant K Nation"

6 Publications

  • Page 1 of 1

APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.

Mol Neurodegener 2021 09 6;16(1):62. Epub 2021 Sep 6.

Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA.

Background: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

Methods: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

Results: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis.

Conclusions: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.
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http://dx.doi.org/10.1186/s13024-021-00483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420022PMC
September 2021

Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Aging Cell 2021 07 12;20(7):e13416. Epub 2021 Jun 12.

Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. Q134R partially inhibited NFAT activity in primary rat astrocytes, but did not prevent CN-mediated dephosphorylation of a non-NFAT target, either in vivo, or in vitro. Acute (≤1 week) oral delivery of Q134R to APP/PS1 (12 months old) or wild-type mice (3-4 months old) infused with oligomeric Aβ peptides led to improved Y maze performance. Chronic (≥3 months) oral delivery of Q134R appeared to be safe, and, in fact, promoted survival in wild-type (WT) mice when given for many months beyond middle age. Finally, chronic delivery of Q134R to APP/PS1 mice during the early stages of amyloid pathology (i.e., between 6 and 9 months) tended to reduce signs of glial reactivity, prevented the upregulation of astrocytic NFAT4, and ameliorated deficits in synaptic strength and plasticity, without noticeably altering parenchymal Aβ plaque pathology. The results suggest that Q134R is a promising drug for treating AD and aging-related disorders.
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http://dx.doi.org/10.1111/acel.13416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282246PMC
July 2021

Oral Gavage Delivery of Stable Isotope Tracer for In Vivo Metabolomics.

Metabolites 2020 Dec 8;10(12). Epub 2020 Dec 8.

Department of Physiology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.

Stable isotope-resolved metabolomics (SIRM) is a powerful tool for understanding disease. Advances in SIRM techniques have improved isotopic delivery and expanded the workflow from exclusively in vitro applications to in vivo methodologies to study systemic metabolism. Here, we report a simple, minimally-invasive and cost-effective method of tracer delivery to study SIRM in vivo in laboratory mice. Following a brief fasting period, we orally administered a solution of [U-C] glucose through a blunt gavage needle without anesthesia, at a physiological dose commonly used for glucose tolerance tests (2 g/kg bodyweight). We defined isotopic enrichment in plasma and tissue at 15, 30, 120, and 240 min post-gavage. C-labeled glucose peaked in plasma around 15 min post-gavage, followed by period of metabolic decay and clearance until 4 h. We demonstrate robust enrichment of a variety of central carbon metabolites in the plasma, brain and liver of C57/BL6 mice, including amino acids, neurotransmitters, and glycolytic and tricarboxylic acid (TCA) cycle intermediates. We then applied this method to study in vivo metabolism in two distinct mouse models of diseases known to involve dysregulation of glucose metabolism: Alzheimer's disease and type II diabetes. By delivering [U-C] glucose via oral gavage to the 5XFAD Alzheimer's disease model and the Lep type II diabetes model, we were able to resolve significant differences in multiple central carbon pathways in both model systems, thus providing evidence of the utility of this method to study diseases with metabolic components. Together, these data clearly demonstrate the efficacy and efficiency of an oral gavage delivery method, and present a clear time course for C enrichment in plasma, liver and brain of mice following oral gavage of [U-C] glucose-data we hope will aid other researchers in their own C-glucose metabolomics study design.
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http://dx.doi.org/10.3390/metabo10120501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764755PMC
December 2020

The effects of mild closed head injuries on tauopathy and cognitive deficits in rodents: Primary results in wild type and rTg4510 mice, and a systematic review.

Exp Neurol 2020 04 11;326:113180. Epub 2020 Jan 11.

Department of Physiology, University of Kentucky, Lexington, KY, United States of America; Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, United States of America. Electronic address:

In humans, the majority of sustained traumatic brain injuries (TBIs) are classified as 'mild' and most often a result of a closed head injury (CHI). The effects of a non-penetrating CHI are not benign and may lead to chronic pathology and behavioral dysfunction, which could be worsened by repeated head injury. Clinical-neuropathological correlation studies provide evidence that conversion of tau into abnormally phosphorylated proteotoxic intermediates (p-tau) could be part of the pathophysiology triggered by a single TBI and enhanced by repeated TBIs. However, the link between p-tau and CHI in rodents remains controversial. To address this question experimentally, we induced a single CHI or two CHIs to WT or rTg4510 mice. We found that 2× CHI increased tau phosphorylation in WT mice and rTg4510 mice. Behavioral characterization in WT mice found chronic deficits in the radial arm water maze in 2× CHI mice that had partially resolved in the 1× CHI mice. Moreover, using Manganese-Enhanced Magnetic Resonance Imaging with R1 mapping - a novel functional neuroimaging technique - we found greater deficits in the rTg4510 mice following 2× CHI compared to 1× CHI. To integrate our findings with prior work in the field, we conducted a systematic review of rodent mild repetitive CHI studies. Following Prisma guidelines, we identified 25 original peer-reviewed papers. Results from our experiments, as well as our systematic review, provide compelling evidence that tau phosphorylation is modified by experimental mild TBI studies; however, changes in p-tau levels are not universally reported. Together, our results provide evidence that repetitive TBIs can result in worse and more persistent neurological deficits compared to a single TBI, but the direct link between the worsened outcome and elevated p-tau could not be established.
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http://dx.doi.org/10.1016/j.expneurol.2020.113180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373372PMC
April 2020

Tau drives translational selectivity by interacting with ribosomal proteins.

Acta Neuropathol 2019 04 13;137(4):571-583. Epub 2019 Feb 13.

Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, BOX 100159, Gainesville, FL, 32610, USA.

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transcriptome and the nascent proteome, and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and found that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis under translational control of rpS6 was reduced under tauopathic conditions in Alzheimer's disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, since regulation of protein synthesis is critical for learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between tauopathies and cognitive impairment.
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http://dx.doi.org/10.1007/s00401-019-01970-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426815PMC
April 2019

Identification of changes in neuronal function as a consequence of aging and tauopathic neurodegeneration using a novel and sensitive magnetic resonance imaging approach.

Neurobiol Aging 2017 08 18;56:78-86. Epub 2017 Apr 18.

Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Epilepsy Center, University of Kentucky, Lexington, KY, USA; Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA; Spinal Cord Injury and Brain Injury Research Center, University of Kentucky, Lexington, KY, USA. Electronic address:

Tauopathies, the most common of which is Alzheimer's disease (AD), constitute the most crippling neurodegenerative threat to our aging population. Tauopathic patients have significant cognitive decline accompanied by irreversible and severe brain atrophy, and it is thought that neuronal dysfunction begins years before diagnosis. Our current understanding of tauopathies has yielded promising therapeutic interventions but have all failed in clinical trials. This is partly due to the inability to identify and intervene in an effective therapeutic window early in the disease process. A major challenge that contributes to the definition of an early therapeutic window is limited technologies. To address these challenges, we modified and adapted a manganese-enhanced magnetic resonance imaging (MEMRI) approach to provide sensitive and quantitative power to detect changes in broad neuronal function in aging mice. Considering that tau tangle burden correlates well with cognitive impairment in Alzheimer's patients, we performed our MEMRI approach in a time course of aging mice and an accelerated mouse model of tauopathy. We measured significant changes in broad neuronal function as a consequence of age, and in transgenic mice, before the deposition of bona fide tangles. This MEMRI approach represents the first diagnostic measure of neuronal dysfunction in mice. Successful translation of this technology in the clinic could serve as a sensitive diagnostic tool for the definition of effective therapeutic windows.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524451PMC
August 2017
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