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Energy metabolism and cognitive function

Energy metabolism and cognitive function

Mol Biol Cell ; Among these key Power-packed nutrition Energy metabolism and cognitive function changes in jetabolism and metabolism Eneggy 3456 cognitife, Dark chocolate sensation891415161718 ]. Alzheimers Res Ther. Article CAS Google Scholar Le Douce J, Maugard M, Veran J, Matos M, Jégo P, Vigneron PA, et al. Front Cell Dev Biol ; Neuroscience ; S 19 : Bulk downloads.

Energy metabolism and cognitive function -

This is partly due to difficulties in recording oxygen concentration as well as from confounds in interpreting oxygen consumption imaging signals.

Blood-oxygen-level dependent BOLD fMRI which relies on neurovascular coupling to measure regions of brain activity based on measurements of oxyhemeoglobin and deoxyhemeoglobin consistently generates signals with a post-stimulus undershoot van Zijl et al. The physiological basis of the BOLD undershoot is heavily debated and is likely stimulus-dependent, one theory however suggests that the BOLD undershoot reflects an uncoupling of CBF and energy metabolism.

This is supported by evidence that oxidative metabolism remains elevated post activation after both blood flow and blood volume have returned to baseline Lu et al. Consistent with this, numerous studies have reported similar increases in oxidative metabolism indicating that sustained focal activation raises the rate of oxidative metabolism to a new steady state level Hoge et al.

With dynamic changes in oxygen metabolism occurring during neuronal activity, dynamic changes are likely to be reflected in levels of oxygen concentration, potentially having secondary effects on protein function and gene expression.

Neurons and neuronal functions are generally viewed as highly sensitive to hypoxia with disruption of oxygen supply to the brain causing detrimental damage within minutes.

Under physiological conditions, PtO 2 measurements in rat range from 6 mm Hg to 40 mm Hg within the cortex 6—16 mm Hg in white matter and 19—40 mm Hg in gray matter and from 1 mm Hg to 60 mm Hg across all brain regions with proximal structures displaying large variations in oxygen tension Erecińska and Silver, During embryonic development, oxygen tension is low in the fetal brain 0.

Within the developing brain, oxygen tension acts as a regulator of neurogenesis with low oxygen promoting progenitor expansion in cortical neurogenic regions and decreasing dopaminergic neurogenesis in the midbrain Wagenführ et al.

Additionally, in the adult brain, hypoxic injury caused by ischemic stroke triggers increased neuronal stem cell proliferation and neurogenesis Arvidsson et al.

This evidence supports a role for hypoxia as a regulatory mechanism in neuronal function and indicates that physiological hypoxia occurring in the adult brain may play a functional role. HIF is a heterodimeric complex consisting of a constitutively expressed β subunit shared by a family of three oxygen-sensitive α subunits.

Most widely studied among these is the HIF-1α subunit. HIFα protein is constitutively expressed but is immediately targeted for degradation by HIF prolyl hydroxylases PHDs that associate with and hydroxylate two conserved HIFα proline residues in an oxygen dependent manner Bruick and McKnight, The Von Hippel-Lindau tumor suppressor ubiquitin ligase complex pVHL , subsequently recognizes HIFα causing HIFα ubiquitination and protein degradation Ivan et al.

During hypoxia, though oxygen-limited inactivation of HIF PHD activity, HIFα is no longer targeted by pVHL and is able to accumulate in the cytoplasm before translocating to the nucleus and acting to promote transcription Figure 2.

Within the nervous system HIF-1α and target genes of HIF-1 are widely expressed under hypoxia, but regulation of HIF-1α can differ among neuronal subtypes Bergeron et al. Following hypoxia, HIF-1α has been shown both in vitro and in vivo to be significantly upregulated in interneurons but not in pyramidal neurons and in neuronal and non-neuronal cells it has been established that the redox state of a cell contributes to HIF-1α regulation Welsh et al.

Additionally, during in C. elegans development, hypoxia has been shown to cause defects in axonal migration that occur in a neuronal cell-type specific manner and are dependent on stabilization of Hif-1 by either hypoxia or increased reactive oxygen species ROS; Pocock and Hobert, Being a primary source of reducing agents, glucose is a major contributor to the redox state of a cell and HIF-1α expression in neurons has been shown to increase in a glucose-dependent manner during hypoxia Shi and Liu, ; Guo et al.

There is also a negative relationship between HIF-1α and ROS levels indicating ROS promotes HIF-1α degradation while a reducing environment stabilizes HIF-1α Schafer and Buettner, ; Niecknig et al.

Figure 2. Hypoxia inducible transcription factor regulation. Under normal oxygen conditions hypoxia-inducible factor-1α HIF-1α is hydroxylated by prolyl hydroxylase PHD enzymes and targeted for ubiquitination by the Von Hippel-Lindau tumor suppresser ubiquitin ligase complex pVHL.

During hypoxia or low oxygen conditions, HIF-1α is stabilized, translocates to the nucleus and associates with HIF-β to promote gene expression, targeting genes containing a hypoxia response element HRE.

Ub, ubiquitin; OH, hydroxyl group. ROS are highly reactive free radical molecules that can cause cellular damage through oxidation of lipids, proteins and DNA. ROS production primarily occurs through electron leakage at electron transport chain ETC complexes I or III during normal oxidative respiration.

Within the brain, a high neuronal oxidative rate heightens the potential for ROS production and neurons are especially vulnerable to oxidative damage due to low levels of antioxidant enzymes such as glutathione GSH; Dringen et al.

Neuronal diversion of glucose catabolism from glycolysis to the PPP through Pfkfb3 degradation therefore not only supports oxidative metabolism of lactate but also enhances neuronal antioxidant capacity through production of the reducing agent, NADH. HIF-1α is also involved in this process and acts as a glycolytic enhancer through transcriptional activation of metabolic genes including Pfkfb3 and pyruvate dehydrogenase kinase-1 PDK1 , both positive regulators of glycolysis and the lactate efflux transporter, MCT4 Figure 2 ; Minchenko et al.

As an oxygen-sensitive molecule, which is highly integrated into metabolic processes, HIF-1α is likely to have an important role in brain plasticity, and dysregulation of HIF-1α expression has already been implicated in neuronal activation and learning and memory.

In a rat microarray study, seizures induced by injection of Kainate, a potent glutamate-receptor agonist that causes overstimulation of neurons, resulted in a 2.

In another microarray study HIF-1α was found to be increased 7-fold in mice following environmental enrichment, where mice are exposed to heightened sensory stimulation known to promote neurogenesis and improve performance in memory tasks Rampon et al.

These data support a significant role for hypoxia in neuronal activity, potentially though neurovascular uncoupling and enhanced neuronal oxidative metabolism depleting neuronal oxygen levels. Neurodegenerative disorders encompass a range of conditions characterized by progressive neuronal damage and degeneration as well as neuronal cell death.

Although neurodegenerative disorders vary in the neuronal populations and cognitive or motor functions affected, metabolic dysfunction is a unifying pathology underlying many of these disorders.

AD principally affects short-term working memory and is classified by the presence of two hallmark neuropathologies; extracellular amyloid plaques, formed from aggregation of amyloid Aβ peptide, and intraneuronal neurofibrillary tangles formed from aggregation of hyperphosphorylated tau.

In AD patients, regional hypometabolism in the brain is a predictor for progressive cognitive decline and reduced cerebral metabolism is associated with carriers of the AD risk allele of the APOE-4 gene Small et al. At the cellular level, mitochondria MC isolated from AD patients display reduced enzymatic activity of the ETC complex IV cytochrome C oxidase; Parker et al.

Similarly, in mouse models of AD, oxidative respiration is diminished and Aβ is found to localize and progressively accumulate in neuronal MC Mucke et al.

This progressive accumulation of Aβ in MC is associated with reduced oxidative respiration and reduced activity of the rate-limiting TCA cycle enzyme, α-ketoglutarate dehydrogenase complex KGDHC , and the pyruvate dehydrogenase complex PDHC , which generates acetyl-CoA for entry into the TCA cycle Casley et al.

Both metabolic dysfunction and mitochondrial Aβ accumulation appear to occur early in disease progression, preceding the onset of extracellular plaque formation Wirths et al. This indicates that early metabolic dysfunction is a key process in AD progression and a potential target for therapeutic intervention.

Also preceding extracellular plaque formation in the AD brain significantly increased ROS production and oxidative stress. Substantially increased ROS activity and oxidative damage is consistently detected in AD patients by various measures Hensley et al.

Increased oxidative stress occurs early in disease progression being observed in patients with mild AD as well as in cases of mild cognitive impairment, at high-risk of developing AD Baldeiras et al.

The pathological Aβ is also known to be a source of ROS production and a cause of neuronal oxidative damage in AD Behl et al. Related to oxidative stress, and also implicated in AD pathology, is dysregulated homeostasis of redox transition metal ions including zinc, copper and iron Schrag et al.

Both elevation and deficiency of zinc is associated with AD and evidence suggests that altered compartmentalization of zinc rather than altered zinc levels may be the cause of zinc pathology in AD Suh et al.

This is supported by dysregulation of numerous zinc transporters in AD patient brains Lovell et al. Zinc has important roles in normal neuronal function and is co-released along with glutamate at the synapse Vogt et al.

A major role of zinc is its significant antioxidant capacity, such that zinc deficiency is linked to neuronal oxidative stress Aimo et al.

Like zinc, copper elevation and copper deficiency have both been associated with AD as well as co-localization of copper with Aβ plaques Miller et al. Copper is also modulated by synaptic activation in neurons and both zinc and copper are able to bind Aβ Schlief et al.

In AD pathology, copper enhances Aβ toxicity and copper:Aβ complexes are a source of ROS production and oxidative damage in neurons Dikalov et al. The redox active iron, although vital for cellular function, is also a pro-oxidant and promotes generation of highly reactive hydroxyl radicals from hydrogen peroxide.

Elevated levels of brain iron in the AD brain as well as iron association with Aβ plaques and neurofibrillary tangles have been detected in various studies Smith et al.

Recently, elevated iron has been shown to predict AD progression and elevated iron was linked to the APOE-4 AD risk allele suggesting it may have a pathological role in AD Ayton et al. Another common feature of AD that contributes to AD pathology is vascular dysfunction.

Cerebrovascular disease, characterized by disrupted blood flow to the brain, significantly increases AD risk and occurs before Aβ accumulation and cognitive decline Arvanitakis et al. In animal models, hypoperfusion also leads to symptoms similar to AD and exacerbates existing AD pathology Walsh et al.

Vascular dysfunction contributes to the pathology of AD due to lower capillary density, meaning narrowed blood vessels and decreased CBF Hamel et al. Diminished blood flow reduces metabolite and oxygen supply to the brain and potentially contributes to build-up of Aβ through impaired clearance of neurotoxic molecules Shibata et al.

Aβ itself is also thought to amplify deficits in CBF and glucose utilization in AD through impairing vasodilation and cerebrovascular autoregulatory mechanisms Niwa et al. Cerebrovascular dysfunction can lead to disrupted oxygen metabolism through hypoperfusion-hypoxia and hypoxia in-turn can enhance AD pathology by promoting tau phosphorylation as well as transcriptionally upregulating the HIF-1 target, β-site β-amyloid precursor protein cleavage enzyme 1 BACE1 that cleaves amyloid precursor protein APP to produce Aβ Figure 3 ; Sun et al.

Figure 3. Disrupted metabolic pathways in neurodegenerative diseases. Aβ accumulates in neuronal mitochondria MC early in disease progression and disrupts oxidative metabolism.

Acetyl-CoA production and tricaboxcylic acid TCA cycle entry is decreased in AD through reduced activity of the pyruvate dehydrogenase complex PDHC. In all three diseases, activity of α-ketoglutarate dehydrogenase complex KGDHC is reduced, reactive oxygen species ROS is increased and transglutaminase TG activity is increased.

TG increases α-synuclein aggregation and reduces oxidative respiration. Aside from rare cases of genetic mutations in familial AD, the major risk factor for developing AD is aging. PD is thought to be caused by both genetic and environmental factors and primarily impacts patient motor function.

PD involves the formation of protein aggregates consisting mainly of α-synuclein and affects the dopaminergic neurons of the midbrain substantia nigra. HD is an inherited neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin HTT gene causing progressive neuronal degeneration and cell death throughout the brain, affecting mood, cognition and motor skills.

Inclusions are also found in the HD brain from aggregation of mutant HTT mHTT protein. Like AD, both PD and HD are associated with increased oxidative stress as well as decreased activity of the KGDHC enzyme Tabrizi et al.

Also, common to all three disorders is increased activity of transglutaminase TG; Johnson et al. TG catalyzes polyamination post-translational modifications of proteins, is known to be increased by ROS and also attenuates HIF-1 signaling Campisi et al.

TG can decrease oxidative metabolism through modification of glycolytic enzymes and is known to cause oxidative stress in HD and aggregation of α-synuclein in PD Cooper et al.

Altered metal ion homeostasis may have a role in PD pathology as well with disrupted levels of both zinc and copper observed in PD patients Brewer et al.

Similar to Aβ, copper also contributes to α-synuclein aggregation and can contribute to oxidative stress through the formation of reactive copper: α-synuclein complexes Wang et al. α-synuclein is also know to exacerbate mitochondrial dysfunction in the presence of toxic oxidizing agents, with loss of α-synuclein in animal models conferring resistance to mitochondrial toxins Klivenyi et al.

Additionally, levels of α-synuclein are increased when oxidative metabolism is inhibited and animal models expressing mutant forms of α-synuclein exhibit neuronal mitochondrial degeneration and cell death Lee et al. In HD, increased oxidative damage to mitochondrial DNA is observed as well as higher frequencies of deletions in the mitochondrial genome and deficits in ETC function with decreased expression of complex II in the striatum and decreased activity of complex IV in striatal and cortical regions Horton et al.

Vascular deficits and disrupted blood flow is a major pathology of HD as well with altered blood vessel density and size found in cortical gray matter, putamen and striatal brain regions.

In HD patients, inclusions of mHTT are also detected in the basal membrane and epithelium of cortical blood vessels and in mouse models of the disease pericytic coverage of cortical and striatal blood vessels is decreased Drouin-Ouellet et al. A number of the metabolic pathologies observed in neurodegenerative disorders are associated with normal aging and may explain the age-related manifestation of neurodegenerative disease phenotypes.

While no longer thought to be directly causative of aging, free radicals and oxidative stress accumulate in the aging brain as in neurodegeneration Smith et al. Mitochondrial function is also linked to aging due to the association of mitochondrial DNA mtDNA haplotypes with longevity and the generation of mtDNA mutator mice that have a premature aging phenotype Trifunovic et al.

It has also been shown there is an increased rate of damaging mutations in mtDNA of post-mitotic aging cells as opposed to aging mitotic cells Greaves et al. While it has been suggested that the somatic rate of mtDNA mutation is unlikely to have a pathological affect due to redundancy in cell mitochondrial numbers, in post-mitotic neurons mtDNA mutation rates are significantly higher than average and, within the cortex, MC with large mtDNA deletions possess a replicative advantage during mitochondrial expansion Song et al.

Aside from AD and PD, deficiency of zinc is also associated with aging, being decreased in the general elderly population Pepersack et al. Diminished CBF occurs in normal aging as well with cortical perfusion found to decrease with age in healthy adults Chen et al.

An age-dependent reduction in perictyes also occurs in mice and is associated with microvascular changes and neurodegeneration Bell et al. Substantial evidence therefore exists supporting disrupted neuronal oxygen supply and oxidative metabolism as a major pathological component of age-related neurodegeneration.

Although it has been well established that metabolic regulation is critical to neuronal function and that metabolic dysfunction is a major pathology in diseases affecting behavior and cognition, there is little known regarding how regulators of metabolism may be involved in neuronal plasticity.

A number of studies, however, support a direct role for metabolic regulation and metabolically linked genes in influencing learning and memory. One of the best examples of this is exposure of hypoxia as a modulator of cognitive performance.

elegans , hypoxia acts as an enhancer of gustatory sensory perception through Hif-1 dependent induction of the neurotransmitter serotonin within specific sensory neurons Pocock and Hobert, In rodent models, exposure to hypobaric hypoxia in adult rats for periods of 7—21 days causes decline in spatial learning similar to aging and is associated with aging-related lipofuscin deposition and ultrastructural changes in MC.

Increasing duration of hypobaric hypoxic exposure also positively correlates with increasing expression of aging markers Biswal et al. Brief hypoxic exposure s in rats also causes synaptic arrest of pyramidal CA1 hippocampal neurons and deficits in spatial memory that are both reversed by blockade of receptors for Adenosine, an inhibitory neurotransmitter Sun et al.

In contrast, long-term facilitation of motor output in adult rats is enhanced by intermittent hypoxia 3 × 3 min intervals, separated by 5 min hyperoxia increasing both phrenic amplitude and burst frequency, which was not observed with a continuous hypoxia of the same cumulative duration Baker and Mitchell, Differing effects of hypoxia in brain plasticity are likely related to differing exposures as well as measurement of different outputs.

Interestingly, mild hypoxia preconditioning confers protection of cognitive abilities during subsequent exposure to severe hypoxia implicating a role for HIFs and transcriptional changes induced by mild hypoxia Rybnikova et al.

Indeed, neuronal knockout of HIF-1α in mice impairs spatial memory and the stabilization of HIF improves hippocampal memory in fear conditioning Tomita et al. Similar learning deficits and age-related changes are also observed in a D-galactose induced model of aging where oxidative injury was the major stimulus for aging Li et al.

Altered expression of lactate metabolic enzymes and transporters is also related to stress induced improvements in cognitive function. Psychological stress, while harmful under chronic conditions, has evolved to enhance cognitive function and improve reactions to stressful situations through hypothalamic activation of adrenergic receptors and hypothalamic-pituitary-adrenal axis glucocorticoid production Dong et al.

Improved cognitive function following short-term stress induction corresponds with β2AR-dependant increases in LDH A, MCT1 and MCT4 expression, the expression of which was modulated by β-arrestin-1 activation of HIF-1α, downstream of β2AR Dong et al.

Altered expression of ETC oxidative phosphorylation genes is also associated with altered behavior in the honeybee. In a study exploring molecular profiles in aggressive honeybee behavior, oxidative phosphorylation was most significantly enriched in association with increased aggression.

This was found to be true for aged bees that display increased aggressive behavior as well as following environmentally enhanced aggression by alarm pheromone exposure and genetic-related aggression occurring in the Africanized honeybee population Alaux et al.

Consistent with this, inhibition of oxidative phosphorylation by treatment with drugs targeting the TCA cycle increased aggression of honeybees measured using an intruder assay Li-Byarlay et al.

In the same study, cell-type-specific knockdown of ETC complex genes using GAL4 drivers in Drosophila found that neuron-specific, but not glia-specific knockdown of the complex I gene NDlike, significantly increased aggressive lunging behavior in flies Li-Byarlay et al.

Also involved in learning and memory are non-coding miRNA genes which are regulated during neuronal activity by various mechanisms and able to regulate translation of various downstream target genes. A number of miRNAs have been associated with plasticity including the hypoxia-regulated, HIF-1 target, miR that is known to be involved in metabolic regulation.

miR is significantly upregulated 24 h after long-term memory formation in the honeybee using an olfactory conditioning paradigm. Upregulation of miR correlated with downregulation of a number of metabolically linked protein-coding genes including Gapdh2, Glucose dehydrogenase, Laccase2 and Aldose reductase-like.

Inhibition of miR by treatment of honeybees with miR antogmiR also resulted in reduced memory retention in the olfactory conditioning assay indicating a functional role in learning and memory Cristino et al. Considering the sensitivity of neurons and neural structures to hypoxia, Cristino et al.

A follow-up study found that in a human-derived neuronal cell-line, miR targeted neurodegeneration-associated genes as well as other plasticity-related genes within the human transcriptome.

This included a number of oxidative metabolism genes, the AD risk-gene APOE as well as the NMDA-R, GRINA , and the human actin homolog, ACTB Watts et al. Another hypoxia-regulated miRNA, miRc, is also associated with modulating cognitive function in rats.

In a model of chronic cerebral hypoperfusion miRc was continuously inhibited, correlating with upregulation of its plasticity-related target gene, TRIM2. Hypoperfusion in this model was associated with deficits in spatial learning that were ameliorated by hippocampal overexpression of miRc Fang et al.

These studies all provide support to the hypothesis that metabolically regulated genes are directly involved in the regulation of neuronal plasticity. While neurovascular coupling mechanisms appear to maintain steady-state oxygen levels in the brain, it is becoming evident that neurovascular uncoupling may in fact have a physiological role in regulating plasticity via oxygen depletion and induction of downstream hypoxia response pathways.

Disruptions to hypoxia and oxidative metabolism have also been extensively attributed to neurodegeneration pathology albeit, there is a lack of understanding, as to how these disruptions are triggered and how they may be therapeutically targeted to halt disease progression and improve cognitive and motor functions.

Altered behavior, including learning and memory, associated with dysregulation of metabolic genes highlights the importance of understanding the role of oxygen metabolism in neuronal plasticity. Further elucidation of how the hypoxia response pathway and other metabolic genes are involved in neuronal function will be critical in determining the molecular links between cognitive function and oxidative metabolism.

This in turn will help elucidate how disrupted metabolism can lead to cognitive deficits and neurodegenerative disease. MW was supported by an Australian Government Research Training Program Stipend Scholarship.

RP was supported by a National Health and Medical Research Council Senior Research Fellowship GNT CC was supported by an Australian Research Council Future Fellowship FT The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Neuroimage 25, — Horton, T. Neurology 45, — Hsiao, H. We found a striking reduction of D,L-α-glycerol-phosphate metabolism in the development of Control astrocytes and in LOAD NPCs, indicating diminished GPDH and G3P shuttle activity to transport reducing equivalents from cytosolic NADH to the ETC [ 33 ].

Mammalian astrocytes express GPDH during development and postnatally [ 41 , 42 , 43 ], and rather than using MAS, seem to mostly rely on the G3P shuttle, which can be activated by glucose and lactate oxidation reviewed in McKenna et al. In contrast, using the iPSC paradigm, our data show that differentiating human astrocytes seem to shift from G3P to MAS activity.

Overall, there were only a few bioenergetic differences between developing Control or LOAD astrocytes; however, there were substantial changes in the bioenergetic activities of LOAD versus Control cells. These changes mainly pertained to a reduction of the glycolytic, CAC, and ETC capacities, and increases in β-oxidation and MAS, which are more pronounced in LOAD astrocytes.

Overall, the striking decrease in G3P shuttle and the increase in MAS and ETC activity in LOAD NPCs, and the increased metabolism of amino acids alanine-glutamine, L-glutamine, and tryptamine, but not L-serine and L-ornithine, which predominantly occurs in LOAD astrocytes, suggest that LOAD cells have major deficits in multiple bioenergetic pathways, including glycolysis, CAC, ETC, and G3P shuttle, for which they seem to compensate by boosting other pathways, notably MAS and β-oxidation, and amino acid metabolism Fig.

It should be noted, however, that a BHB effect could have been masked, as these experiments were not performed under conditions of oxidative stress, starvation, or glucose blockage, which have been associated with shifting energy production to BHB-activated β-oxidation [ 44 ].

The LOAD-associated metabolic alterations observed here could, in part, be the consequences of DEGs. LOAD NPCs and astrocytes exhibit transcriptional deregulation of several molecules in key functions and branch points in bioenergetics processes, such as PGM , HK , and PFKFB3 , which regulate upstream events in glycolysis; LDHA that controls the production of pyruvate; ME that works together with LDH catalyzing the conversion of malate to pyruvate and is essential for NADPH regeneration; PDPR and PDK3 , which are important in oxidative decarboxylation of pyruvate; and GPDH as the determining factor in the G3P shuttle.

In addition, the lack of CAC and complex I- to V-associated DEGs and the predominance of DEGs related to cytochrome p and β-oxidation indicate that the transcriptional deregulation in LOAD affects only certain aspects of the respiratory chain. The exact consequences of these LOAD-associated bioenergetic phenotypes need further investigation; however, to this end, we could show that growth of LOAD NPCs slowed-down after multiple passaging, while both LOAD and Control astrocytes had similar growth patterns.

The diminished growth rate of LOAD NPCs is consistent with data from a recent study by Meyer et al. In sum, LOAD cells have deficits in efficiently producing energy due to impairments in numerous key components of bioenergetic substrate uptake or production, while they seem to enhance alternative pathways for energy production and transport.

Importantly, these changes are inherent, probably body-wide, as also observed in fibroblasts [ 19 ], and already occur in early development, all suggesting that individuals with such altered bioenergetic and metabolic features may be predisposed to the risk and pathophysiology of LOAD.

LOAD may, thus, be a consequence of a lifelong altered and inefficient energy management leading to progressive homeostatic imbalances and associated downstream effects including the inability to sufficiently compensate for neurotoxic insults, all contributing to an aberrant aging process resulting in neural dysfunction and degeneration at the cellular level, and dementia at the cognitive level [ 9 , 10 , 30 , 46 , 47 , 48 ].

The new results presented here provide important details characterizing differences in energy metabolism inherent to cells in those at risk for LOAD.

While developing interventions for multi-hit disorders like LOAD is complicated, the findings presented here offer a platform that could be used to better define and address LOAD-associated pathophysiology. Further study of these abnormalities might determine control points and modulators to normalize bioenergetic functions, aid in developing tests for risk, and could lead to effective preventive measures in LOAD.

Subjects Supplementary Table 1 were recruited at the McLean Hospital Memory Diagnostic Clinic. PBMCs were derived from blood samples and dermal fibroblasts from skin biopsies as described [ 25 ].

All samples were genotyped for APOE. Fibroblasts or PBMCs were reprogrammed to iPSC using the Sendai virus methodology, except for two published lines C1 and C2 [ 25 , 26 ] , which were converted by RNA reprogramming.

All iPSC lines were rigorously characterized for pluripotency. Cells were differentiated and propagated in standard tissue culture. iPSCs were dissociated to single cells to form embryonic bodies from which NPCs were derived. Astrocytes were differentiated from NPCs according to published protocols [ 49 ].

Cell phenotypes were determined by ICC and cell proliferation was measured with a Scepter TM cell counter MilliporeSigma, Burlington, MA. and captured with the Zeiss Axiocam Mono and Zeiss Zen Lite program. To quantify cell surface molecules, CellProfiler version 3.

software was used www. Bioenergetic parameters were determined using Seahorse XFp Cell Mito Stress Tests Seahorse, Agilent Technologies, Santa Clara, CA and the processing of bioenergetic substrates were assessed in Biolog MitoPlate S-1 assays Biolog, Hayward, CA.

Mitochondrial densities were determined with the MitoTracker TM Green FM dye Invitrogen Thermo Fisher Scientific, Waltham, MA. Total RNA was isolated and purified using TRI-Reagent MilliporeSigma and RNA integrity was measured with an Agilent Bioanalyzer Agilent.

RNA was used for qRT-PCR and in RNA-Seq performed on an Illumina NovaSeq system. aspx or PRISM 8 for macOS Version 8. Differences of comparison were considered statistically significant when p values were less than 0. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al.

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Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G. Identification of a novel human nicotinamide mononucleotide adenylyltransferase. Biochemical Biophysical Res Commun. Article CAS Google Scholar. Download references. This study was supported by the Program for Neuropsychiatric Research, McLean Hospital BMC and NRF grants R1A2B, R1H1A, IITP grant from MSIT HS.

The authors want to thank Ryan A. Healy, Yoon Lee, Wang Liao, Miseon Oh, and Jinfeng Xuan for technical, and Suzanne Babb, Fontini Savvides, and Tamare V. Adrien for administrative help.

The authors also thank Dr. Rosario Sanchez-Pernaute and Dr. Christian LeGuern for critically reading the manuscript and helpful discussions.

Department of Psychiatry, Harvard Medical School, Belmont, MA, USA. Woo-In Ryu, Mariana K. Bormann, Minqi Shen, Brent Forester, Kai-C. Basic Neuroscience Division, Harvard Medical School, Belmont, MA, USA. Program for Neuropsychiatric Research, McLean Hospital, Harvard Medical School, Belmont, MA, USA.

Bormann, Minqi Shen, Kai-C. Department of Immunology, Tufts University School of Medicine, Boston, MA, USA. Mood Disorders Division and Geriatric Psychiatry Research Program, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Department of Molecular and Life Sciences, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, South Korea.

Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. You can also search for this author in PubMed Google Scholar. All authors reviewed the manuscript. KCS and BMC conceptualized and designed, and BMC funded the study.

WIR, MKB, MS, DK, YP, and JS performed the experiments. KCS, WIR, MKB, and HS analyzed and interpreted the data, and KCS wrote the paper.

BF recruited and diagnosed subjects. Correspondence to Kai-C. Sonntag or Bruce M. Open Access This article is licensed under a Creative Commons Attribution 4.

Reprints and permissions. Ryu, WI. et al. Mol Psychiatry 26 , — Download citation. Received : 20 August Revised : 01 March Accepted : 18 March Published : 16 April Issue Date : October Anyone you share the following link with will be able to read this content:.

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Signal Transduction and Targeted Therapy Skip to main content Thank you for visiting nature. nature molecular psychiatry articles article. Download PDF.

Subjects Biochemistry Cell biology Diseases Neuroscience Stem cells. Full size image. Discussion LOAD is a complexly determined disorder characterized by a combination of multiple interacting pathological processes, some of which are genetically determined and inherent in neurodevelopment and in youth and some of which are part of the normal aging process.

Methods Subject population and cell derivation Subjects Supplementary Table 1 were recruited at the McLean Hospital Memory Diagnostic Clinic. Cell culture Cells were differentiated and propagated in standard tissue culture.

Epidemiological, neuropathological, and functional neuroimaging evidence implicates cognitivve and regional disruptions in xognitive metabolism and energetics in the pathogenesis of Acai berry benefits impairment. Herbal medicine and phytochemicals cell microcircuits Dark chocolate sensation modified cognitice excitatory dognitive inhibitory synaptic activity and neurotrophic Dark chocolate sensation. Ageing and Vunction disease cause Mwtabolism in cellular energy metabolism, Eneergy of excitation or inhibition, and neurotrophic factor release, which overwhelm compensatory mechanisms and result in dysfunction of neuronal microcircuits and brain networks. A prolonged positive energy balance impairs the ability of neurons to adapt to oxidative and metabolic stress. Results from experimental studies in animals show how disruptions caused by chronic positive energy balance, such as diabetes, lead to accelerated cognitive ageing and Alzheimer's disease. Therapeutic interventions to allay cognitive dysfunction that target energy metabolism and adaptive stress responses such as neurotrophin signalling have been effective in animal models and in preliminary studies in humans.

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Metabolism \u0026 Nutrition, Part 1: Crash Course Anatomy \u0026 Physiology #36 Dynamic metabolic changes Energy metabolism and cognitive function in functioj are critically important in congitive brain plasticity and cognitive fknction. In other tissue types, disruptions to metabolism and the resultant changes in metaboliam oxidative state, such as increased Heightened fat metabolism rate oxygen species ROS or induction of Energy metabolism and cognitive function, are associated with cellular stress. In the brain however, where drastic metabolic shifts occur to support physiological processes, subsequent changes to cellular oxidative state and induction of transcriptional sensors of oxidative stress likely play a significant role in regulating physiological neuronal function. Understanding the role of metabolism and metabolically-regulated genes in neuronal function will be critical in elucidating how cognitive functions are disrupted in pathological conditions where neuronal metabolism is affected. Here, we discuss known mechanisms regulating neuronal metabolism as well as the role of hypoxia and oxidative stress during normal and disrupted neuronal function. Energy metabolism and cognitive function

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