bims-medebr 2024-11-24 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–11–24
23 papers selected by
Regina F. Fernández, Johns Hopkins University

Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention.
L-Proline Alters Energy Metabolism in Brain Cortical Tissue Slices.
ATP Restoration by ATP-Deprived Cultured Primary Astrocytes.
Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders.
Tak1 licenses mitochondrial transfer from astrocytes to POMC neurons to maintain glucose and cholesterol homeostasis.
Altered markers of brain metabolism and excitability are associated with executive functioning in young children exposed to alcohol in utero.
Differential Effects of Itaconate and its Esters on the Glutathione and Glucose Metabolism of Cultured Primary Rat Astrocytes.
Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.
Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects.
Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.
Mitochondrial plasticity: An emergent concept in neuronal plasticity and memory.
Hepatic encephalopathy as a result of ammonia-induced increase in GABAergic tone with secondary reduced brain energy metabolism.
Development of a novel glucose-dendrimer based therapeutic targeting hyperexcitable neurons in neurological disorders.
Neuronal fatty acid-binding protein enhances autophagy and suppresses amyloid-β pathology in a Drosophila model of Alzheimer's disease.
Brain and behavioural anomalies caused by Tbx1 haploinsufficiency are corrected by vitamin B12.
Fueling neurodegeneration: metabolic insights into microglia functions.
Impact of aerobic exercise on brain metabolism: Insights from spatial metabolomic analysis.
Presynaptic terminal integrity is associated with glucose metabolism in Parkinson's disease.
Synaptic and cognitive impairment associated with L444P heterozygous glucocerebrosidase mutation.
Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.
Loss of tissue-type plasminogen activator causes multiple developmental anomalies.
An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Exp Neurol. 2024 Nov 18. pii: S0014-4886(24)00390-X. [Epub ahead of print] 115064

Diminished lactate utilization in LDHB-deficient neurons leads to impaired long-term memory retention.

Jin Soo Lee, Bok Seon Yoon, Songmi Han, Yihyang Kim, Chan Bae Park.

  Neurons' high energy demands for processing, transmitting, and storing information in the brain necessitate efficient energy metabolism to maintain normal neuronal function. The astrocyte-neuron lactate shuttle (ANLS) hypothesis suggests neurons preferentially use lactate from astrocytes over glucose for energy. This study investigated lactate dehydrogenase B (LDHB), which preferentially converts lactate to pyruvate, in neuronal energy metabolism and cognitive function. LDHB-deficient neurons showed reduced lactate-driven energy metabolism in culture, while LDHB-deficient brains accumulated lactate, both indicating decreased lactate utilization. This reduced lactate utilization was correlated with impaired long-term memory in LDHB-deficient mice, while short-term memory remained unaffected and overall neuropathology was only mildly disturbed. Unexpectedly, LDHB-deficient neurons maintain stable energy metabolism under physiological glucose conditions, indicating the presence of lactate dehydrogenase (LDH) activity in LDHB-deficient neurons. The observation of lactate dehydrogenase A (LDHA), which preferentially converts pyruvate to lactate but can also catalyze the reverse reaction less efficiently, in LDHB-deficient neurons may explain their stable energy metabolism and reduced lactate utilization. This study challenges the established concept of strict LDH isoform compartmentalization in brain cells, questioning the exclusive presence of LDHB in neurons and suggesting a more flexible neuronal metabolic profile than previously assumed by the ANSL hypothesis.

Keywords:  Astrocyte-neuron lactate shuttle; Lactate; Lactate dehydrogenase B; Long-term memory retention; Metabolic compartmentalization

DOI:  https://doi.org/10.1016/j.expneurol.2024.115064
Neurochem Res. 2024 Nov 18. 50(1): 16

L-Proline Alters Energy Metabolism in Brain Cortical Tissue Slices.

Abhijit Das, Gregory Gauthier-Coles, Stefan Bröer, Caroline D Rae.

  L-Proline (L-Pro) is a non-essential amino acid which, in high concentrations, can cause neurological problems including seizures, although the causative mechanism for this is unclear. Here, we studied the impact of physiological levels of proline on brain energy metabolism and investigated the metabolism of L-Pro itself, using the cortical brain tissue slice and stable isotope labelling from [1-13 C]glucose and [1,2-13 C]acetate detected by NMR spectroscopy and LCMS. L-Pro was actively taken up by the slices and significantly reduced the total metabolic pools of all measured metabolites with glutamine the least affected, while reducing net flux of 13C into glycolytic byproducts (lactate and alanine). Conversely, net flux into Krebs cycle intermediates was increased, suggesting that L-Pro at lower concentrations was driving increased mitochondrial activity in both neurons and glia at the expense of glycolysis and metabolic pool sizes. As there was no evidence of metabolism of [1-13 C] L-Pro in slices under normo-glycemic conditions, the effect of proline on metabolism was not due to displacement of metabolites by added L-Pro. Comparison of the metabolic fingerprint generated by L-Pro in slices metabolizing [3-13 C]pyruvate with that generated by ligands active in the GABAergic system suggested that L-Pro may engender effects similar to that of the inhibitory neurotransmitter and metabolite γ-aminobutyric acid (GABA), in line with previous suggestions that L-Pro may be a GABA mimetic in addition to its role as a modulator of mitochondrial metabolism.

Keywords:  Acetate; GABA; Glucose; NMR spectroscopy; Proline

DOI:  https://doi.org/10.1007/s11064-024-04262-1
Neurochem Res. 2024 Nov 16. 50(1): 13

ATP Restoration by ATP-Deprived Cultured Primary Astrocytes.

Gabriele Karger, Johanna Elisabeth Willker, Antonia Regina Harders, Patrick Watermann, Ralf Dringen.

  A high cellular concentration of adenosine triphosphate (ATP) is essential to fuel many important functions of brain astrocytes. Although cellular ATP depletion has frequently been reported for astrocytes, little is known on the metabolic pathways that contribute to ATP restoration by ATP-depleted astrocytes. Incubation of cultured primary rat astrocytes in glucose-free buffer for 60 min with the mitochondrial uncoupler BAM15 lowered the cellular ATP content by around 70%, the total amount of adenosine phosphates by around 50% and the adenylate energy charge (AEC) from 0.9 to 0.6. Testing for ATP restoration after removal of the uncoupler revealed that the presence of glucose as exclusive substrate allowed the cells to restore within 6 h around 80% of the initial ATP content, while coapplication of adenosine plus glucose enabled the cells to fully restore their initial ATP content within 60 min. A rapid but incomplete and transient ATP restoration was found for astrocytes that had been exposed to adenosine alone. This restoration was completely prevented by application of the pyruvate uptake inhibitor UK5099, the respiratory chain inhibitor antimycin A or by the continuous presence of BAM15. However, the presence of these compounds strongly accelerated the release of lactate from the cells, suggesting that the ribose moiety of adenosine can serve as substrate to fuel some ATP restoration via mitochondrial metabolism. Finally, the adenosine-accelerated ATP restoration in glucose-fed astrocytes was inhibited by the presence of the adenosine kinase inhibitor ABT-702. These data demonstrate that astrocytes require for a rapid and complete ATP restoration the presence of both glucose as substrate and adenosine as AMP precursor.

Keywords:  ATP restoration; Adenosine; Astrocytes; Glycolysis; Metabolism; Mitochondria

DOI:  https://doi.org/10.1007/s11064-024-04276-9
Mol Neurodegener. 2024 Nov 19. 19(1): 85

Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders.

Melanie Loix, Sam Vanherle, Marta Turri, Stephan Kemp, Karl J L Fernandes, Jerome J A Hendriks, Jeroen F J Bogie.

  Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.

Keywords:  Cellular and molecular dysfunction; Fatty acid metabolism; Neurodegenerative disorders; Stearoyl-CoA desaturases

DOI:  https://doi.org/10.1186/s13024-024-00778-w
Cell Rep. 2024 Nov 19. pii: S2211-1247(24)01334-2. [Epub ahead of print]43(12): 114983

Tak1 licenses mitochondrial transfer from astrocytes to POMC neurons to maintain glucose and cholesterol homeostasis.

Kaili Yin, Tingting Zhang, Xiyuan Lu, Qing Shen, Kaiyue Gu, Ying Huang, Chaonan Li, Jingyi Hou, Juxue Li, Guo Zhang.

  It remains incompletely understood how the astrocytes in the mediobasal hypothalamus (MBH) regulate systemic glucose and cholesterol metabolism. Here, we show that MBH astrocytic Tak1 (transforming growth factor β [TGF-β]-activated kinase 1) controls the metabolism of glucose and cholesterol. Tak1 is expressed in MBH astrocytes and activated after a short-term nutritional excess. In chow-fed mice, astrocytic deletion of Tak1 across the brain or its suppression in the MBH impairs glucose tolerance, reduces insulin sensitivity, and results in hypercholesterolemia. Astrocytic Tak1 activation in the MBH alleviates these symptoms in mice fed a high-fat diet (HFD). We show that astrocytic Tak1 modulates the activity of proopiomelanocortin (POMC) neurons and enables the transport of mitochondria from astrocytes to POMC neurons. In astrocytic Tak1 knockout mice, supplementation of CD38, a molecule that is crucial in mitochondrial transfer, restores glucose and cholesterol homeostasis. Overall, these findings highlight an important role of MBH astrocytic Tak1 in glucose and cholesterol metabolism.

Keywords:  CP: Metabolism; CP: Neuroscience; Tak1; astrocyte; glucose homeostasis; hypothalamus; mitochondrial transfer

DOI:  https://doi.org/10.1016/j.celrep.2024.114983
Metab Brain Dis. 2024 Nov 21. 40(1): 30

Altered markers of brain metabolism and excitability are associated with executive functioning in young children exposed to alcohol in utero.

Meaghan V Perdue, Mohammad Ghasoub, Madison Long, Marilena M DeMayo, Tiffany K Bell, Carly A McMorris, Deborah Dewey, W Ben Gibbard, Christina Tortorelli, Ashley D Harris, Catherine Lebel.

  Prenatal alcohol exposure (PAE) is the leading known cause of birth defects and cognitive disabilities, with impacts on brain development and executive functioning. Abnormalities in structural and functional brain features are well-documented in children with PAE, but the effects of PAE on brain metabolism in children have received less attention. Levels of brain metabolites can be measured non-invasively using magnetic resonance spectroscopy (MRS). Here, we present the first study of PAE-related brain metabolite differences in early childhood (ages 3-8 years) and their associations with cognitive performance, including executive functioning (EF) and pre-reading skills. We measured metabolites in two cohorts of children with PAE and unexposed children using MRS in the anterior cingulate cortex (ACC; cohort 1) and left temporo-parietal cortex (LTP; cohort 2). Total choline (tCho), a marker of membrane/myelin metabolism, was elevated in both regions in children with PAE compared to unexposed children, and glutamate + glutamine (Glx), a marker of excitability, was elevated in the ACC. The PAE group exhibited more difficulties with EF, and higher tCho was associated with better EF in both PAE and unexposed groups. In addition, elevated Glx in the ACC was associated with poorer inhibitory control within the PAE group only. LTP metabolites were not significantly associated with pre-reading skills in PAE or unexposed groups. Together, these findings point to altered membrane metabolism and excitability in young children with PAE. These findings provide new insight to potential mechanisms by which PAE disrupts brain development and cognitive functioning in early childhood.

Keywords:  Alcohol; Childhood; Cognition; Magnetic Resonance Spectroscopy (MRS); Metabolism

DOI:  https://doi.org/10.1007/s11011-024-01432-6
Neurochem Res. 2024 Nov 20. 50(1): 24

Differential Effects of Itaconate and its Esters on the Glutathione and Glucose Metabolism of Cultured Primary Rat Astrocytes.

Patrick Watermann, Gurleen K Kalsi, Ralf Dringen, Christian Arend.

  Itaconate is produced as endogenous metabolite by decarboxylation of the citric acid cycle intermediate cis-aconitate. As itaconate has anti-microbial and anti-inflammatory properties, this substance is considered as potential therapeutic drug for the treatment of inflammation in various diseases including traumatic brain injury and stroke. To test for potential adverse effects of itaconate on the viability and metabolism of brain cells, we investigated whether itaconate or its membrane permeable derivatives dimethyl itaconate (DI) and 4-octyl itaconate (OI) may affect the basal glucose and glutathione (GSH) metabolism of cultured primary astrocytes. Acute exposure of astrocytes to itaconate, DI or OI in concentrations of up to 300 µM for up to 6 h did not compromise cell viability. Of the tested substances, only OI stimulated aerobic glycolysis as shown by a time- and concentration-dependent increase in glucose-consumption and lactate release. None of the tested itaconates affected the pentose-phosphate pathway-dependent reduction of the water-soluble tetrazolium salt 1 (WST1). In contrast, both DI and OI, but not itaconate, depleted cellular GSH in a time- and concentration-dependent manner. For OI this depletion was accompanied by a matching increase in the extracellular GSH content that was completely prevented in the presence of the multidrug resistance protein 1 (Mrp1)-inhibitor MK571, while in DI-treated cultures GSH was depleted both in cells and medium. These data suggest that OI stimulates Mrp1-mediated astrocytic GSH export, while DI reacts with GSH to a conjugate that is not detectable by the GSH assay applied. The data presented demonstrate that itaconate, DI and OI differ strongly in their effects on the GSH and glucose metabolism of cultured astrocytes. Such results should be considered in the context of the discussed potential use of such compounds as therapeutic agents.

Keywords:  Astrocytes; Glutathione; Glycolysis; Itaconate; Pentose-phosphate pathway

DOI:  https://doi.org/10.1007/s11064-024-04263-0
Antioxid Redox Signal. 2024 Nov 22.

Myelin Lipid Alterations in Neurodegenerative Diseases: Landscape and Pathogenic Implications.

Ziying Xu, Sijia He, Mst Marium Begum, Xianlin Han.

  Significance: Lipids, which constitute the highest portion (over 50%) of brain dry mass, are crucial for brain integrity, energy homeostasis, and signaling regulation. Emerging evidence revealed that lipid profile alterations and abnormal lipid metabolism occur during normal aging and in different forms of neurodegenerative diseases. Moreover, increasing genome-wide association studies have validated new targets on lipid-associated pathways involved in disease development. Myelin, the protective sheath surrounding axons, is crucial for efficient neural signaling transduction. As the primary site enriched with lipids, impairments of myelin are increasingly recognized as playing significant and complex roles in various neurodegenerative diseases, beyond simply being secondary effects of neuronal loss. Recent Advances: With advances in the lipidomics field, myelin lipid alterations and their roles in contributing to or reflecting the progression of diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and others, have recently caught great attention. Critical Issues: This review summarizes recent findings of myelin lipid alterations in the five most common neurodegenerative diseases and discusses their implications in disease pathogenesis. Future Directions: By highlighting myelin lipid abnormalities in neurodegenerative diseases, this review aims to encourage further research focused on lipids and the development of new lipid-oriented therapeutic approaches in this area. Antioxid. Redox Signal. 00, 000-000.

Keywords:  aging; central nervous system; lipidomics; lipids; metabolism; neurodegeneration

DOI:  https://doi.org/10.1089/ars.2024.0676
bioRxiv. 2024 Nov 01. pii: 2024.11.01.621496. [Epub ahead of print]

Defective Neurogenesis in Lowe Syndrome is Caused by Mitochondria Loss and Cilia-related Sonic Hedgehog Defects.

Chien-Hui Lo, Siyu Chen, Jingyu Zhao, Zhiquan Liu, Biao Wang, Qing Wang, Tia J Kowal, Yang Sun.

Human brain development is a complex process that requires intricate coordination of multiple cellular and developmental events. Dysfunction of lipid metabolism can lead to neurodevelopmental disorders. Lowe syndrome (LS) is a recessive X-linked disorder associated with proximal tubular renal disease, congenital cataracts and glaucoma, and central nervous system developmental delays. Mutations in OCRL, which encodes an inositol polyphosphate 5-phosphatase, lead to the development of LS. The cellular mechanism responsible for neuronal dysfunction in LS is unknown. Here we show depletion of mitochondrial DNA and decrease in mitochondrial activities result in neuronal differentiation defects. Increased astrocytes, which are secondary responders to neurodegeneration, are observed in neuronal (iN) cells differentiated from Lowe patient-derived iPSCs and an LS mouse model. Inactivation of cilia-related sonic hedgehog signaling, which organizes the pattern of cellular neuronal differentiation, is observed in an OCRL knockout, iN cells differentiated from Lowe patient-derived iPSCs, and an LS mouse model. Taken together, our findings indicate that mitochondrial dysfunction and impairment of the ciliary sonic hedgehog signaling pathway represent a novel pathogenic mechanism underlying the disrupted neuronal differentiation observed in LS.

DOI: https://doi.org/10.1101/2024.11.01.621496
bioRxiv. 2024 Nov 07. pii: 2024.11.06.622291. [Epub ahead of print]

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Ozan Baytas, Shawn M Davidson, Julie A Kauer, Eric M Morrow.

Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2- null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2- null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2- null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.

DOI: https://doi.org/10.1101/2024.11.06.622291
Mol Neurobiol. 2024 Nov 19.

The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.

Patrick C Bradshaw, Jessa L Aldridge, Leah E Jamerson, Canah McNeal, A Catherine Pearson, Chad R Frasier.

  Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.

Keywords:  Alzheimer’s; Cardiolipin; Cell death; Inflammation; Mitochondria; Parkinson’s

DOI:  https://doi.org/10.1007/s12035-024-04630-6
Neurobiol Dis. 2024 Nov 16. pii: S0969-9961(24)00342-5. [Epub ahead of print] 106740

Mitochondrial plasticity: An emergent concept in neuronal plasticity and memory.

Typhaine Comyn, Thomas Preat, Alice Pavlowsky, Pierre-Yves Plaçais.

  Mitochondria are classically viewed as 'on demand' energy suppliers to neurons in support of their activity. In order to adapt to a wide range of demands, mitochondria need to be highly dynamic and capable of adjusting their metabolic activity, shape, and localization. Although these plastic properties give them a central support role in basal neuronal physiology, recent lines of evidence point toward a role for mitochondria in the regulation of high-order cognitive functions such as memory formation. In this review, we discuss the interplay between mitochondrial function and neural plasticity in sustaining memory formation at the molecular and cellular levels. First, we explore the global significance of mitochondria in memory formation. Then, we will detail the memory-relevant cellular and molecular mechanisms of mitochondrial plasticity. Finally, we focus on those mitochondrial functions, including but not limited to ATP production, that give mitochondria their pivotal role in memory formation. Altogether, this review highlights the central role of mitochondrial structural and functional plasticity in supporting and regulating neuronal plasticity and memory.

Keywords:  Energy; Glia; Memory; Mitochondria dynamics; TCA cycle

DOI:  https://doi.org/10.1016/j.nbd.2024.106740
Metab Brain Dis. 2024 Nov 19. 40(1): 19

Hepatic encephalopathy as a result of ammonia-induced increase in GABAergic tone with secondary reduced brain energy metabolism.

Michael Sørensen, Jens Velde Andersen, Peter Nissen Bjerring, Hendrik Vilstrup.

  Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver insufficiency and/or portosystemic shunting. HE is mostly episodic and as such reversible. Hyperammonemia clearly plays a key role in the pathophysiology, but the precise detrimental events in the brain leading to HE remain equivocal. Several pathogenic models have been proposed, but few have been linked to clinical studies and observations. Decreased oxygen metabolism is observed in both type A and C HE and in this review, we advocate that this reflects an actual reduced oxygen demand and not a primary cause of HE. As driving force, we propose that the hyperammonemia via astrocytic glutamine synthetase causes an increased γ-aminobutyric acid (GABA) mediated neuro-inhibition which subsequently leads to an overall decreased energy demand of the brain, something that can be enhanced by concomitant neuroinflammation. This also explains the reversibility of the condition.

Keywords:  CBF; Glutamine; Liver insufficiency; Organic delirium; Oxygen demand

DOI:  https://doi.org/10.1007/s11011-024-01473-x
Bioeng Transl Med. 2024 Sep;9(5): e10655

Development of a novel glucose-dendrimer based therapeutic targeting hyperexcitable neurons in neurological disorders.

Anjali Sharma, Nirnath Sah, Rishi Sharma, Preeti Vyas, Wathsala Liyanage, Sujatha Kannan, Rangaramanujam M Kannan.

  Neuronal hyperexcitability and excitotoxicity lies at the core of debilitating brain disorders such as epilepsy and traumatic brain injury, culminating in neuronal death and compromised brain function. Overcoming this challenge requires a unique approach that selectively restores normal neuronal activity and rescues neurons from impending damage. However, delivering drugs selectively to hyperexcitable neurons has been a challenge, even upon local administration. Here, we demonstrate the remarkable ability of a novel, scalable, generation-two glucose-dendrimer (GD2) made primarily of glucose and ethylene glycol building blocks, to specifically target hyperexcitable neurons in primary culture, ex vivo acute brain slices, and in vivo mouse models of acute seizures. Pharmacology experiments in ex vivo brain slices suggest GD2 uptake in neurons is mediated through glucose transporters (GLUT and SGLT). Inspired by these findings, we conjugated GD2 with a potent anti-epileptic drug, valproic acid (GD2-VPA), for efficacy studies in the pilocarpine-mouse model of seizure. When delivered intranasally, GD2-VPA significantly decreased the seizure-severity. In summary, our findings demonstrate the unique selectivity of glucose dendrimers in targeting hyperexcitable neurons, even upon intranasal delivery, laying the foundation for neuron-specific therapies for the precise protection and restoration of neuronal function, for targeted neuroprotection.

Keywords:  brain injury; dendrimer; glucose dendrimer‐valproic acid conjugate; nanoparticle; seizure

DOI:  https://doi.org/10.1002/btm2.10655
PLoS Genet. 2024 Nov;20(11): e1011475

Neuronal fatty acid-binding protein enhances autophagy and suppresses amyloid-β pathology in a Drosophila model of Alzheimer's disease.

Seokhui Jang, Byoungyun Choi, Chaejin Lim, Minkyoung Kim, Ji-Eun Lee, Hyungi Lee, Eunji Baek, Kyoung Sang Cho.

Fatty acid-binding proteins (FABPs) are small cytoplasmic proteins involved in intracellular lipid transport and bind free fatty acids, cholesterol, and retinoids. FABP3, the major neuronal FABP in the adult brain, is upregulated in the CSF of patients with Alzheimer's disease (AD). However, the precise role of neuronal FABPs in AD pathogenesis remains unclear. This study investigates the contribution of fabp, the Drosophila homolog of FABP3 and FABP7, to amyloid β (Aβ) pathology using a Drosophila model. Neuronal knockdown of fabp shortened the lifespan of flies and increased age-related protein aggregates in the brain. In an AD model, fabp knockdown in neurons increased Aβ accumulation and Aβ-induced neurodegeneration, whereas fabp overexpression ameliorated Aβ pathology. Notably, fabp overexpression stimulated autophagy, which was inhibited by the knockdown of Eip75B, the Drosophila homolog of the peroxisome proliferator-activated receptor (PPAR). The PPAR activator rosiglitazone restored autophagy impaired by fabp knockdown and reduced fabp knockdown-induced increased Aβ aggregation and cell death. Furthermore, knockdown of either fabp or Eip75B in the wing imaginal disc or adult fly brain reduced the expression of Atg6 and Atg8a. Additionally, treatment of the fabp knockdown AD model flies with polyunsaturated fatty acids, such as docosahexaenoic acid or linoleic acid, partially alleviated cell death in the developing eye, restored impaired autophagy flux, reduced Aβ aggregation, and attenuated Aβ-induced cell death. Our results suggest that Drosophila fabp plays an important role in maintaining protein homeostasis during aging and protects neurons from Aβ-induced cell death by enhancing autophagy through the PPAR pathway. These findings highlight the potential importance of neuronal FABP function in AD pathogenesis.

DOI: https://doi.org/10.1371/journal.pgen.1011475
Life Sci Alliance. 2025 Feb;pii: e202403075. [Epub ahead of print]8(2):

Brain and behavioural anomalies caused by Tbx1 haploinsufficiency are corrected by vitamin B12.

Marianna Caterino, Debora Paris, Giulia Torromino, Michele Costanzo, Gemma Flore, Annabella Tramice, Elisabetta Golini, Silvia Mandillo, Diletta Cavezza, Claudia Angelini, Margherita Ruoppolo, Andrea Motta, Elvira De Leonibus, Antonio Baldini, Elizabeth Illingworth, Gabriella Lania.

The brain-related phenotypes observed in 22q11.2 deletion syndrome (DS) patients are highly variable, and their origin is poorly understood. Changes in brain metabolism might contribute to these phenotypes, as many of the deleted genes are involved in metabolic processes, but this is unknown. This study shows for the first time that Tbx1 haploinsufficiency causes brain metabolic imbalance. We studied two mouse models of 22q11.2DS using mass spectrometry, nuclear magnetic resonance spectroscopy, and transcriptomics. We found that Tbx1 +/- mice and Df1/+ mice, with a multigenic deletion that includes Tbx1, have elevated brain methylmalonic acid, which is highly brain-toxic. Focusing on Tbx1 mutants, we found that they also have a more general brain metabolomic imbalance that affects key metabolic pathways, such as glutamine-glutamate and fatty acid metabolism. We provide transcriptomic evidence of a genotype-vitamin B12 treatment interaction. In addition, vitamin B12 treatment rescued a behavioural anomaly in Tbx1 +/- mice. Further studies will be required to establish whether the specific metabolites affected by Tbx1 haploinsufficiency are potential biomarkers of brain disease status in 22q11.2DS patients.

DOI: https://doi.org/10.26508/lsa.202403075
J Neuroinflammation. 2024 Nov 17. 21(1): 300

Fueling neurodegeneration: metabolic insights into microglia functions.

Mohammadamin Sadeghdoust, Aysika Das, Deepak Kumar Kaushik.

  Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.

Keywords:  Immunometabolism; Microglia; Neurodegenerative diseases; Neuroinflammation; Therapeutic strategies

DOI:  https://doi.org/10.1186/s12974-024-03296-0
Behav Brain Res. 2024 Nov 15. pii: S0166-4328(24)00495-9. [Epub ahead of print]478 115339

Impact of aerobic exercise on brain metabolism: Insights from spatial metabolomic analysis.

Jiaping Zheng, Wei Luo, Chenghua Kong, Wenhuo Xie, Xiuyun Chen, Jiaxian Qiu, Kexin Wang, Hong Wei, Yu Zhou.

   BACKGROUND: Exercise is acknowledged for its beneficial effects on brain health; however, the intricate underlying molecular mechanisms remain poorly understood.
AIMS: This study aimed to explore aerobic exercise-induced metabolic alterations in the brain.
METHODS: We conducted an eight-week treadmill running exercise program in two-month-old male C57/BL6J mice. Body weight, serum lipid, glucose levels, and spatial cognition were measured. Spatial metabolomic analysis was performed to compare the metabolomic profiles across different brain regions. Immunohistochemical methods were used to compare the expression of carnitine palmitoyltransferase 1c (CPT1c).
RESULTS: Exercise induced significant changes in the analysed metabolomic profiles. There were 904 differentially expressed metabolites (DEMs) detected in the whole brain section. Notable alterations in lipid profiles were observed, and among the 292 lipids detected, there were 74 (25.34 %), 85 (29.11 %), and 78 (26.71 %) lipids differentially expressed in the hippocampus, thalamus, and hypothalamus of the Exe group, respectively. Lipid metabolism related pathways and enzymes were also altered, with L-carnitine and CPT1c upregulated in the three regions (p<0.05), and epinephrine levels decreased in the hippocampus (p<0.05). Furthermore, the vitamin B6 metabolism pathway was altered in the hypothalamus.
CONCLUSIONS: This study highlighted the significant changes in lipid metabolism induced by involuntary exercise in the brains of young male mice. Exercise also altered epinephrine levels and the vitamin B12 metabolic pathway in specific brain regions, which indicated the multifaceted effects of exercise on the brain.

Keywords:  Epinephrine; Exercise; L-carnitine; Spatial metabolomics; Vitamin B6 metabolism

DOI:  https://doi.org/10.1016/j.bbr.2024.115339
Eur J Nucl Med Mol Imaging. 2024 Nov 22.

Presynaptic terminal integrity is associated with glucose metabolism in Parkinson's disease.

Weiyi Wang, Yanru Wang, Limin Xu, Xueling Liu, Yuqing Hu, Junpeng Li, Qi Huang, Shuhua Ren, Yiyun Huang, Yihui Guan, Yuxin Li, Fengchun Hua, Qing Ye, Fang Xie.

   OBJECTIVE: To investigate the relationship of synaptic loss with glucose metabolism and dopaminergic transporters in Parkinson's disease (PD) patients.
METHODS: A total of 16 patients with PD and 11 age-matched healthy controls underwent positron emission tomography (PET) with the tracers [18F]SynVesT-1, a ligand for the presynaptic terminal marker synaptic vesicle protein 2 A (SV2A), and FDG. PD patients also underwent PET with the dopamine transporter (DAT) ligand [18F]FP-CIT. The difference in synaptic density between PD patients and age-matched normal controls(NCs) was determined in the selected regions of interest, and the correlations of the [18F]SynVesT-1 PET SUVRs with [18F]FP-CIT PET SUVRs and [18F]FDG PET SUVRs were evaluated.
RESULTS: Compared with that in the NC group, the synaptic density in the caudate region was significantly lower in the PD group (SUVR: 2.51 ± 0.36 vs. 3.18 ± 0.32, p < 0.001), especially in the pre-commissural caudate and post-commissural caudate (SUVR: 2.42 ± 0.29 vs. 2.63 ± 0.32, p < 0.01; 0.76 ± 0.31 vs. 0.97 ± 0.33, p < 0.001). A reduced synaptic density was significantly correlated with DAT (r = 0.61, p < 0.001) and glucose metabolism (r = 0.73, p < 0.001) in the post-commissural caudate. In the post-commissural regions of the caudate, there was a partial mediating effect of synaptic density on the relationship between glucose metabolism and DAT availability (indirect effect: β4 = 0.039, p = 0.024).
CONCLUSION: [18F]SynVesT-1 binds specifically to SV2A, reflecting synaptic density, and there is a positive correlation metabolic pattern related to the changes reflected by [18F]SynVesT-1 and [18F]FDG.

Keywords:  Dopaminergic transporter; Glucose metabolism; Parkinson’s disease; Synaptic vesicle protein 2A

DOI:  https://doi.org/10.1007/s00259-024-06993-3
Brain. 2024 Nov 20. pii: awae380. [Epub ahead of print]

Synaptic and cognitive impairment associated with L444P heterozygous glucocerebrosidase mutation.

Wudu Lado, Ahrom Ham, Hongyu Li, Hong Zhang, Audrey Yuen Chang, Sergio Pablo Sardi, Roy N Alcalay, Ottavio Arancio, Serge Przedborsky, Guomei Tang.

  Cognitive impairment is a common but poorly understood non-motor aspect of Parkinson's disease, negatively affecting patient's functional capacity and quality of life. The mechanisms underlying cognitive impairment in Parkinson's disease are still elusive, limiting treatment and prevention strategies. This study investigates the molecular and cellular basis of cognitive impairment associated with heterozygous mutations in GBA1, the strongest risk gene for Parkinson's disease that encodes glucocerebrosidase (GCase), a lysosome enzyme that degrades the glycosphingolipid glucosylceramide into glucose and ceramide. Using a Gba1L444P/+ mouse model, we provide evidence that L444P heterozygous Gba1 mutation (L444P/+) causes hippocampus-dependent spatial and reference memory deficits independently of α-synuclein (αSyn) accumulation, GCase lipid substrate accumulation, dopaminergic dysfunction and motor deficits. The mutation disrupts hippocampal synaptic plasticity and basal synaptic transmission by reducing the density of hippocampal CA3-CA1 synapses, a mechanism that is dissociated from αSyn-mediated presynaptic neurotransmitter release. Using a well-characterized Thy1-αSyn pre-manifest Parkinson's disease mouse model overexpressing wild type human αSyn, we find that the L444P/+ mutation exacerbates hippocampal synaptic αSyn accumulation, synaptic and cognitive impairment in young Gba1L444P/+:Thy1-αSyn double mutant animals. With age, Thy1-αSyn mice manifest motor symptoms, and the double mutant mice exhibit more exacerbated synaptic and motor impairment than the Thy1-αSyn mice. Taken together, our results suggest that heterozygous L444P GBA1 mutation alone perturbs hippocampal synaptic structure and function, imposing a subclinical pathological burden for cognitive impairment. When co-existing αSyn overexpression is present, heterozygous L444P GBA1 mutation interacts with αSyn pathology to accelerate Parkinson's disease-related cognitive impairment and motor symptoms.

Keywords:   GBA1-associated Parkinson’s disease; memory deficit; neurodegeneration; synapse loss; synaptic plasticity

DOI:  https://doi.org/10.1093/brain/awae380
Cancer Metab. 2024 Nov 19. 12(1): 35

Glutaminolysis is associated with mitochondrial pathway activation and can be therapeutically targeted in glioblastoma.

Kenji Miki, Mikako Yagi, Ryusuke Hatae, Ryosuke Otsuji, Takahiro Miyazaki, Katsuhiro Goto, Daiki Setoyama, Yutaka Fujioka, Yuhei Sangatsuda, Daisuke Kuga, Nayuta Higa, Tomoko Takajo, Yonezawa Hajime, Toshiaki Akahane, Akihide Tanimoto, Ryosuke Hanaya, Yuya Kunisaki, Takeshi Uchiumi, Koji Yoshimoto.

   BACKGROUND: Glioblastoma is an aggressive cancer that originates from abnormal cell growth in the brain and requires metabolic reprogramming to support tumor growth. Metabolic reprogramming involves the upregulation of various metabolic pathways. Although the activation of specific metabolic pathways in glioblastoma cell lines has been documented, the comprehensive profile of metabolic reprogramming and the role of each pathway in glioblastoma tissues in patients remain elusive.
METHODS: We analyzed 38 glioblastoma tissues. As a test set, we examined 20 tissues from Kyushu University Hospital, focusing on proteins related to several metabolic pathways, including glycolysis, the one-carbon cycle, glutaminolysis, and the mitochondrial tricarboxylic acid cycle. Subsequently, we analyzed an additional 18 glioblastoma tissues from Kagoshima University Hospital as a validation set. We also validated our findings using six cell lines, including U87, LN229, U373, T98G, and two patient-derived cells.
RESULTS: The levels of mitochondria-related proteins (COX1, COX2, and DRP1) were correlated with each other and with glutaminolysis-related proteins (GLDH and GLS1). Conversely, their expression was inversely correlated with that of glycolytic proteins. Notably, inhibiting the glutaminolysis pathway in cell lines with high GLDH and GLS1 expression proved effective in suppressing tumor growth.
CONCLUSIONS: Our findings confirm that glioblastoma tissues can be categorized into glycolytic-dominant and mitochondrial-dominant types, as previously reported. The mitochondrial-dominant type is also glutaminolysis-dominant. Therefore, inhibiting the glutaminolysis pathway may be an effective treatment for mitochondrial-dominant glioblastoma.

Keywords:  Glioblastoma; Glutaminolysis; Metabolic changes; Mitochondria

DOI:  https://doi.org/10.1186/s40170-024-00364-0
Brain Commun. 2024 ;6(6): fcae408

Loss of tissue-type plasminogen activator causes multiple developmental anomalies.

Kevin Uguen, Tanja Frey, Osama Muthaffar, Jean-Claude Décarie, Najim Ameziane, Sarah Boissel, Yalda Baradaran-Heravi, Anita Rauch, Gabriela Oprea, Aboulfazl Rad, Katharina Steindl, Jacques L Michaud.

  Hydrocephalus and Dandy-Walker malformation are amongst the most common congenital brain anomalies. We identified three consanguineous families with both obstructive hydrocephalus and Dandy-Walker malformation. To understand the molecular basis of these anomalies, we conducted genome-wide sequencing in these families. We identified three homozygous truncating variants in the PLAT gene in the four affected family members. All of them showed tetraventricular hydrocephalus. In two individuals, a membrane at the inferior aspect of the fourth ventricle was likely the cause of their hydrocephalus. Three cases exhibited Dandy-Walker malformation, whereas the two oldest individuals displayed intellectual disability. PLAT encodes the tissue-type plasminogen activator, a serine protease whose main function is to cleave the proenzyme plasminogen to produce active plasmin. Interestingly, plasminogen deficiency has also been shown to cause obstructive hydrocephalus and Dandy-Walker malformation, suggesting that loss of PLAT causes these defects by disrupting plasmin production. In summary, we describe a recessive disorder characterized by obstructive hydrocephalus, Dandy-Walker malformation and intellectual disability in individuals with loss-of-function variants in PLAT. This discovery further strengthens the involvement of the plasminogen pathway in the pathogenesis of these developmental disorders.

Keywords:  Dandy–Walker malformation; PLAT; hydrocephalus; intellectual disability; plasminogen

DOI:  https://doi.org/10.1093/braincomms/fcae408
bioRxiv. 2024 Nov 03. pii: 2024.10.31.621317. [Epub ahead of print]

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells.

Faith C Kaluba, Thomas J Rogers, Yu-Jin Jeong, Althea Waldhart, Kelly H Sokol, Cameron J Lee, Samuel R Daniels, Joseph Longo, Amy Johnson, Ryan D Sheldon, Russell G Jones, Evan C Lien.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.

DOI: https://doi.org/10.1101/2024.10.31.621317