bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023‒05‒21
forty-four papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Measuring brain docosahexaenoic acid turnover as a marker of metabolic consumption.
  2. Targeting PDK2 rescues stress-induced impaired brain energy metabolism.
  3. Sex-Dimorphic Octadecaneuropeptide (ODN) Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neuron Function and Counterregulatory Hormone Secretion.
  4. Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
  5. Brain glucose metabolism and dopamine transporter changes in rats with morphine-induced conditioned place preference.
  6. Mitochondrial Dysfunction, Altered Mitochondrial Oxygen, and Energy Metabolism Associated with the Pathogenesis of Schizophrenia.
  7. CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease.
  8. Mapping of exogenous choline uptake and metabolism in rat glioblastoma using deuterium metabolic imaging (DMI).
  9. Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice.
  10. Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.
  11. Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis.
  12. Activation of TRPV4 channels promotes the loss of cellular ATP in organotypic slices of the mouse neocortex exposed to chemical ischemia.
  13. Lipidomic Alterations in the Cerebral Cortex and White Matter in Sporadic Alzheimer's Disease.
  14. The effect of neuroinflammation on the cerebral metabolism at baseline and after neural stimulation in neurodegenerative diseases.
  15. Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in Sod1 mutant mouse model of ALS.
  16. The SphK1/S1P axis regulates synaptic vesicle endocytosis via TRPC5 channels.
  17. Appraising the Role of Astrocytes as Suppliers of Neuronal Glutathione Precursors.
  18. Impact of acute stress on murine metabolomics and metabolic flux.
  19. Niemann-Pick type C disease: Case report and review of the literature.
  20. Metabolic Disturbance of High-Saturated Fatty Acid Diet in Cognitive Preservation.
  21. Neuronal Senescence in the Aged Brain.
  22. Connecting Dots between Mitochondrial Dysfunction and Depression.
  23. Regulation of neural stem cell differentiation and brain development by MGAT5-mediated N-glycosylation.
  24. Accelerated Breakdown of Phosphatidylcholine and Phosphatidylethanolamine Is a Predominant Brain Metabolic Defect in Alzheimer's Disease.
  25. Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?
  26. Cholesterol efflux mechanism revealed by structural analysis of human ABCA1 conformational states.
  27. Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis.
  28. Ameliorating Mitochondrial Dysfunction of Neurons by Biomimetic Targeting Nanoparticles Mediated Mitochondrial Biogenesis to Boost the Therapy of Parkinson's Disease.
  29. Role of de novo lipogenesis in inflammation and insulin resistance in alzheimer's disease.
  30. Elevated galectin-3 is associated with aging, multiple sclerosis, and oxidized phosphatidylcholine induced neurodegeneration.
  31. Systemic Metabolism and Mitochondria in the Mechanism of Alzheimer's Disease: Finding Potential Therapeutic Targets.
  32. Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain.
  33. The Regulation of GLT-1 Degradation Pathway by SIRT4.
  34. Changes in Plasma Neutral and Ether-Linked Lipids Are Associated with The Pathology and Progression of Alzheimer's Disease.
  35. Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners.
  36. Alpha-linolenic acid enhances the facilitation of GABAergic neurotransmission in the BLA and CA1.
  37. N-Acetylaspartate and Choline Metabolites in Cortical and Subcortical Regions in Clinical High Risk Relative to Healthy Control Subjects: An Exploratory 7T MRSI Study.
  38. The local GLP-1 system in the olfactory bulb is required for odor-evoked cephalic phase of insulin release in mice.
  39. The Multifunctional Family of Mammalian Fatty Acid-Binding Proteins.
  40. What Are the Roles of Pericytes in the Neurovascular Unit and Its Disorders?
  41. Anticonvulsant Profile of Selected Medium-Chain Fatty Acids (MCFAs) Co-Administered with Metformin in Mice in Acute and Chronic Treatment.
  42. Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.
  43. The Effects of PP2A Disruption on ER-Mitochondria Contact and Mitochondrial Functions in Neuronal-like Cells.
  44. Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.
  1. Pharmacol Ther. 2023 May 16. pii: S0163-7258(23)00101-8. [Epub ahead of print] 108437
    Measuring brain docosahexaenoic acid turnover as a marker of metabolic consumption.
    Brinley J Klievik, Aidan D Tyrrell, Chuck T Chen, Richard P Bazinet.
      Docosahexaenoic acid (DHA, 22:6n-3) accretion in brain phospholipids is critical for maintaining the structural fluidity that permits proper assembly of protein complexes for signaling. Furthermore, membrane DHA can by released by phospholipase A2 and act as substrate for synthesis of bioactive metabolites that regulate synaptogenesis, neurogenesis, inflammation, and oxidative stress. Thus, brain DHA is consumed through multiple pathways including mitochondrial β-oxidation, autoxidation to neuroprostanes, as well as enzymatic synthesis of bioactive metabolites including oxylipins, synaptamide, fatty-acid amides, and epoxides. By using models developed by Rapoport and colleagues, brain DHA loss has been estimated to be 0.07-0.26 μmol DHA/g brain/d. Since β-oxidation of DHA in the brain is relatively low, a large portion of brain DHA loss may be attributed to synthesis of autoxidative and bioactive metabolites. In recent years, we have developed a novel application of compound specific isotope analysis to trace DHA metabolism. By the use of natural abundance in 13C-DHA in food supply, we are able to trace brain phospholipid DHA loss in free-living mice with estimates ranging from 0.11 to 0.38 μmol DHA/g brain/d, in reasonable agreement with previous methods. This novel fatty acid metabolic tracing methodology should improve our understanding of the factors that regulate brain DHA metabolism.
    Keywords:  Compound specific isotope analysis (CSIA); DHA metabolism; Kinetic modeling; Oxylipins; Specialized pro-resolving mediators
    DOI:  https://doi.org/10.1016/j.pharmthera.2023.108437
  2. Mol Psychiatry. 2023 May 15.
    Targeting PDK2 rescues stress-induced impaired brain energy metabolism.
    Changshui Wang, Changmeng Cui, Pengfei Xu, Li Zhu, Hongjia Xue, Beibei Chen, Pei Jiang.
      Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.
    DOI:  https://doi.org/10.1038/s41380-023-02098-9
  3. ASN Neuro. 2023 Jan-Dec;15:15 17590914231167230
    Sex-Dimorphic Octadecaneuropeptide (ODN) Regulation of Ventromedial Hypothalamic Nucleus Glucoregulatory Neuron Function and Counterregulatory Hormone Secretion.
    Karen P Briski, Prabhat R Napit, Abdulrahman Alhamyani, Jérôme Leprince, A S M Hasan Mahmood.
      Central endozepinergic signaling is implicated in glucose homeostasis. Ventromedial hypothalamic nucleus (VMN) metabolic monitoring governs glucose counter-regulation. VMN glucose-stimulatory nitric oxide (NO) and glucose-inhibitory γ-aminobutyric acid (GABA) neurons express the energy gauge 5'-AMP-activated protein kinase (AMPK). Current research addresses the premise that the astrocyte glio-peptide octadecaneuropeptide (ODN) imposes sex-dimorphic control of metabolic sensor activity and neurotransmitter signaling in these neurons. The ODN G-protein coupled-receptor antagonist cyclo(1-8)[DLeu5]OP (LV-1075) was administered intracerebroventricularly (icv) to euglycemic rats of each sex; additional groups were pretreated icv with the ODN isoactive surrogate ODN11-18 (OP) before insulin-induced hypoglycemia. Western blotting of laser-catapult-microdissected VMN NO and GABA neurons showed that hypoglycemia caused OP-reversible augmentation of phospho-, e.g., activated AMPK and nitric oxide synthase (nNOS) expression in rostral (female) or middle (male) VMN segments or ODN-dependent suppression of nNOS in male caudal VMN. OP prevented hypoglycemic down-regulation of glutamate decarboxylase profiles in female rat rostral VMN, without affecting AMPK activity. LV-1075 treatment of male, not female rats elevated plasma glucagon and corticosterone concentrations. Moreover, OP attenuated hypoglycemia-associated augmentation of these hormones in males only. Results identify, for each sex, regional VMN metabolic transmitter signals that are subject to endozepinergic regulation. Directional shifts and gain-or-loss of ODN control during eu- versus hypoglycemia infer that VMN neuron receptivity to or post-receptor processing of this stimulus may be modulated by energy state. In male, counter-regulatory hormone secretion may be governed principally by ODN-sensitive neural pathways, whereas this endocrine outflow may be controlled by parallel, redundant ODN-dependent and -independent mechanisms in female.
    Keywords:  AMPK; cyclo(1−8)[DLeu5]OP; insulin-induced hypoglycemia; neuronal nitric oxide synthase; octadecaneuropeptide; sex differences; ventromedial hypothalamic nucleus
    DOI:  https://doi.org/10.1177/17590914231167230
  4. Cells. 2023 05 06. pii: 1329. [Epub ahead of print]12(9):
    Cellular and Mitochondrial NAD Homeostasis in Health and Disease.
    Jaylyn Waddell, Rehana Khatoon, Tibor Kristian.
      The mitochondrion has a unique position among other cellular organelles due to its dynamic properties and symbiotic nature, which is reflected in an active exchange of metabolites and cofactors between the rest of the intracellular compartments. The mitochondrial energy metabolism is greatly dependent on nicotinamide adenine dinucleotide (NAD) as a cofactor that is essential for both the activity of respiratory and TCA cycle enzymes. The NAD level is determined by the rate of NAD synthesis, the activity of NAD-consuming enzymes, and the exchange rate between the individual subcellular compartments. In this review, we discuss the NAD synthesis pathways, the NAD degradation enzymes, and NAD subcellular localization, as well as NAD transport mechanisms with a focus on mitochondria. Finally, the effect of the pathologic depletion of mitochondrial NAD pools on mitochondrial proteins' post-translational modifications and its role in neurodegeneration will be reviewed. Understanding the physiological constraints and mechanisms of NAD maintenance and the exchange between subcellular compartments is critical given NAD's broad effects and roles in health and disease.
    Keywords:  NAD; brain; mitochondria
    DOI:  https://doi.org/10.3390/cells12091329
  5. Addict Biol. 2023 May;28(5): e13277
    Brain glucose metabolism and dopamine transporter changes in rats with morphine-induced conditioned place preference.
    Da Shao, Donglang Jiang, Qi Huang, Shuhua Ren, Junpeng Li, Jianfei Xiao, Yihui Guan, Bin Lai, Jun Zhao, Fang Xie, Fengchun Hua.
      Addiction to morphine is a chronic brain disease leading to compulsive abuse. Drug addiction animal models with and without conditioned place preference (CPP) training have been used to investigate cue-elicited drug craving. We used 18 F-fluorodeoxyglucose (18 F-FDG) and 11 C-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (11 C-CFT) micro-PET/CT scans to examine the regional changes in brain glucose metabolism and dopamine transporter (DAT) availability to study their relationship underlying drug memory in morphine-treated rat models with and without CPP. Standardized uptake value ratio (SUVr) of 18 F-FDG significantly decreased in the medial prefrontal cortex (mPFC) and cingulate with short-term morphine administration compared with the baseline condition. Voxelwise analysis indicated glucose metabolism alterations in the somatosensory cortex, hippocampus and cingulate in morphine-treated rats and in the striatum, thalamus, medial prefrontal cortex, primary motor cortex and many regions in the cortex in the CPP group compared with the baseline condition. Alterative glucose metabolism was also observed in the striatum, primary somatosensory cortex and some cortical regions in the CPP group compared with morphine alone group. DAT expression alterations were only observed in the long-term morphine compared with the short-term morphine group. This study shows that cerebral glucose metabolism significantly altered during morphine administration and CPP process mainly in the mPFC, striatum and hippocampus, which indicates that the function of these brain regions is involved in cue-induced craving and memory retrieval.
    Keywords:  hippocampal and neocortical circuits; memory retrieval; morphine; striatum
    DOI:  https://doi.org/10.1111/adb.13277
  6. Int J Mol Sci. 2023 Apr 28. pii: 7991. [Epub ahead of print]24(9):
    Mitochondrial Dysfunction, Altered Mitochondrial Oxygen, and Energy Metabolism Associated with the Pathogenesis of Schizophrenia.
    Iveta Fizíková, Jozef Dragašek, Peter Račay.
      The significant complexity of the brain can lead to the development of serious neuropsychiatric disorders, including schizophrenia. A number of mechanisms are involved in the etiopathogenesis of schizophrenia, pointing to its complexity and opening a new perspective on studying this disorder. In this review of currently published studies, we focused on the contribution of mitochondria to the process, with an emphasis on oxidative damage, ROS, and energy metabolism. In addition, we point out the influence of redox imbalance, which can lead to the occurrence of oxidative stress with increased lipid peroxidation, linked to the formation of toxic aldehydes such as 4-hydroxynonenal (4-HNE) and HNE protein adducts. We also analysed the role of lactate in the process of energy metabolism and cognitive functions in schizophrenia.
    Keywords:  energy metabolism; mitochondria; oxidative stress; schizophrenia
    DOI:  https://doi.org/10.3390/ijms24097991
  7. Cells. 2023 04 29. pii: 1287. [Epub ahead of print]12(9):
    CRMP2 Participates in Regulating Mitochondrial Morphology and Motility in Alzheimer's Disease.
    Tatiana Brustovetsky, Rajesh Khanna, Nickolay Brustovetsky.
      Mitochondrial bioenergetics and dynamics (alterations in morphology and motility of mitochondria) play critical roles in neuronal reactions to varying energy requirements in health and disease. In Alzheimer's disease (AD), mitochondria undergo excessive fission and become less motile. The mechanisms leading to these alterations are not completely clear. Here, we show that collapsin response mediator protein 2 (CRMP2) is hyperphosphorylated in AD and that is accompanied by a decreased interaction of CRMP2 with Drp1, Miro 2, and Mitofusin 2, which are proteins involved in regulating mitochondrial morphology and motility. CRMP2 was hyperphosphorylated in postmortem brain tissues of AD patients, in brain lysates, and in cultured cortical neurons from the double transgenic APP/PS1 mice, an AD mouse model. CRMP2 hyperphosphorylation and dissociation from its binding partners correlated with increased Drp1 recruitment to mitochondria, augmented mitochondrial fragmentation, and reduced mitochondrial motility. (S)-lacosamide ((S)-LCM), a small molecule that binds to CRMP2, decreased its phosphorylation at Ser 522 and Thr 509/514, and restored CRMP2's interaction with Miro 2, Drp1, and Mitofusin 2. This was paralleled by decreased Drp1 recruitment to mitochondria, diminished mitochondrial fragmentation, and improved motility of the organelles. Additionally, (S)-LCM-protected cultured cortical AD neurons from cell death. Thus, our data suggest that CRMP2, in a phosphorylation-dependent manner, participates in the regulation of mitochondrial morphology and motility, and modulates neuronal survival in AD.
    Keywords:  Alzheimer’s disease; CRMP2; cortical neurons; mitochondrial morphology; mitochondrial motility; neuronal cell death
    DOI:  https://doi.org/10.3390/cells12091287
  8. Front Cell Neurosci. 2023 ;17 1130816
    Mapping of exogenous choline uptake and metabolism in rat glioblastoma using deuterium metabolic imaging (DMI).
    Kevan L Ip, Monique A Thomas, Kevin L Behar, Robin A de Graaf, Henk M De Feyter.
      Introduction: There is a lack of robust metabolic imaging techniques that can be routinely applied to characterize lesions in patients with brain tumors. Here we explore in an animal model of glioblastoma the feasibility to detect uptake and metabolism of deuterated choline and describe the tumor-to-brain image contrast.Methods: RG2 cells were incubated with choline and the level of intracellular choline and its metabolites measured in cell extracts using high resolution 1H NMR. In rats with orthotopically implanted RG2 tumors deuterium metabolic imaging (DMI) was applied in vivo during, as well as 1 day after, intravenous infusion of 2H9-choline. In parallel experiments, RG2-bearing rats were infused with [1,1',2,2'-2H4]-choline and tissue metabolite extracts analyzed with high resolution 2H NMR to identify molecule-specific 2H-labeling in choline and its metabolites.
    Results: In vitro experiments indicated high uptake and fast phosphorylation of exogenous choline in RG2 cells. In vivo DMI studies revealed a high signal from the 2H-labeled pool of choline + metabolites (total choline, 2H-tCho) in the tumor lesion but not in normal brain. Quantitative DMI-based metabolic maps of 2H-tCho showed high tumor-to-brain image contrast in maps acquired both during, and 24 h after deuterated choline infusion. High resolution 2H NMR revealed that DMI data acquired during 2H-choline infusion consists of free choline and phosphocholine, while the data acquired 24 h later represent phosphocholine and glycerophosphocholine.
    Discussion: Uptake and metabolism of exogenous choline was high in RG2 tumors compared to normal brain, resulting in high tumor-to-brain image contrast on DMI-based metabolic maps. By varying the timing of DMI data acquisition relative to the start of the deuterated choline infusion, the metabolic maps can be weighted toward detection of choline uptake or choline metabolism. These proof-of-principle experiments highlight the potential of using deuterated choline combined with DMI to metabolically characterize brain tumors.
    Keywords:  cancer; choline; deuterium; glioblastoma; metabolic imaging
    DOI:  https://doi.org/10.3389/fncel.2023.1130816
  9. Cells. 2023 04 08. pii: 1111. [Epub ahead of print]12(8):
    Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice.
    Jessica Panes, Thi Kim Oanh Nguyen, Huanyao Gao, Trace A Christensen, Andrea Stojakovic, Sergey Trushin, Jeffrey L Salisbury, Jorge Fuentealba, Eugenia Trushina.
      Alzheimer's disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.
    Keywords:  Alzheimer’s disease (AD); endoplasmic reticulum (ER); mitochondria; serial block-face scanning electron microscopy (SBFSEM); small molecule mitochondria targeted therapeutics; three-dimensional electron microscopy (3DEM)
    DOI:  https://doi.org/10.3390/cells12081111
  10. CNS Neurosci Ther. 2023 May 19.
    Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.
    Yitong Li, Yue Li, Lei Chen, Yi Li, Kaixi Liu, Jingshu Hong, Qian Wang, Ning Kang, Yanan Song, Xinning Mi, Yi Yuan, Dengyang Han, Taotao Liu, Ning Yang, Xiangyang Guo, Zhengqian Li.
      INTRODUCTION: Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats.METHODS: Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi-1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function.
    RESULTS: Surgery impaired hippocampal-dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi-1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function.
    CONCLUSION: Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR.
    Keywords:  aged rats; delayed neurocognitive recovery; mitochondrial dysfunction; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.1111/cns.14261
  11. Cells. 2023 04 19. pii: 1188. [Epub ahead of print]12(8):
    Reversing Dysdynamism to Interrupt Mitochondrial Degeneration in Amyotrophic Lateral Sclerosis.
    Gerald W Dorn.
      Amyotrophic lateral sclerosis is one of several chronic neurodegenerative conditions in which mitochondrial abnormalities are posited to contribute to disease progression. Therapeutic options targeting mitochondria include enhancing metabolism, suppressing reactive oxygen production and disrupting mitochondria-mediated programmed cell death pathways. Herein is reviewed mechanistic evidence supporting a meaningful pathophysiological role for the constellation of abnormal mitochondrial fusion, fission and transport, collectively designated mitochondrial dysdynamism, in ALS. Following this is a discussion on preclinical studies in ALS mice that seemingly validate the idea that normalizing mitochondrial dynamism can delay ALS by interrupting a vicious cycle of mitochondrial degeneration, leading to neuronal die-back and death. Finally, the relative benefits of suppressing mitochondrial fusion vs. enhancing mitochondrial fusion in ALS are speculated upon, and the paper concludes with the prediction that the two approaches could be additive or synergistic, although a side-by-side comparative trial may be challenging to perform.
    Keywords:  mitochondrial fission; mitochondrial fusion; mitochondrial transport; mitophagy
    DOI:  https://doi.org/10.3390/cells12081188
  12. J Physiol. 2023 May 17.
    Activation of TRPV4 channels promotes the loss of cellular ATP in organotypic slices of the mouse neocortex exposed to chemical ischemia.
    Nils Pape, Christine R Rose.
      The vertebrate brain has an exceptionally high energy need. During ischemia, intracellular ATP concentrations decline rapidly, resulting in the breakdown of ion gradients and cellular damage. Here, we employed the nanosensor ATeam1.03YEMK to analyse the pathways driving the loss of ATP upon transient metabolic inhibition in neurons and astrocytes of the mouse neocortex. We demonstrate that brief chemical ischemia, induced by combined inhibition of glycolysis and oxidative phosphorylation, results in a transient decrease in intracellular ATP. Neurons experienced a larger relative decline and showed less ability to recover from prolonged (>5 minutes) metabolic inhibition than astrocytes. Blocking voltage-gated Na+ channels or NMDA receptors ameliorated the ATP decline in neurons and astrocytes, while blocking glutamate uptake aggravated the overall reduction in neuronal ATP, confirming the central role of excitatory neuronal activity in the cellular energy loss. Unexpectedly, pharmacological inhibition of transient receptor potential vanilloid 4 (TRPV4) channels significantly reduced the ischemia-induced decline in ATP in both cell types. Imaging with Na+ -sensitive indicator dye ING-2 furthermore showed that TRPV4 inhibition also reduced ischemia-induced increases in intracellular Na+ . Altogether, our results demonstrate that neurons exhibit a higher vulnerability to brief metabolic inhibition than astrocytes. Moreover, they reveal an unexpected strong contribution of TRPV4 channels to the loss of cellular ATP and suggest that the demonstrated TRPV4-related ATP consumption is most likely a direct consequence of Na+ influx. Activation of TRPV4 channels thus provides a hitherto unacknowledged contribution to the cellular energy loss during energy failure, generating a significant metabolic cost in ischemic conditions. KEY POINTS: In the ischemic brain, cellular ATP concentrations decline rapidly, which results in the collapse of ion gradients and promotes cellular damage and death. We analysed the pathways driving the loss of ATP upon transient metabolic inhibition in neurons and astrocytes of the mouse neocortex. Our results confirm the central role of excitatory neuronal activity in the cellular energy loss and demonstrate that neurons experience a larger decline in ATP and are more vulnerable to brief metabolic stress than astrocytes. Our study also reveals a new, previously unknown involvement of osmotically-activated transient receptor potential vanilloid 4 (TRPV4) channels to the reduction in cellular ATP in both cell types and indicates that this is a consequence of TRPV4-mediated Na+ influx. We conclude that activation of TRPV4 channels provides a considerable contribution to the cellular energy loss, thereby generating a significant metabolic cost in ischemic conditions. Abstract figure legend We show that brief chemical ischemia, induced by combined inhibition of glycolysis and oxidative phosphorylation results in a transient decrease in cellular ATP of neurons and astrocytes of the murine neocortex. The decline in ATP is promoted by activation of NMDA receptors (NMDA-R), of voltage-gated Na+ channels (Nav) in neurons and of excitatory amino acid transporters (EAATs) in astrocytes. In addition, our study reveals that transient receptor potential vanilloid 4 (TRPV4) channels contribute to the ischemia-induced ATP decline in both cell types. Our data furthermore suggests that the TRPV4-related decline in cellular ATP is caused by TRPV4-related Na+ influx. This article is protected by copyright. All rights reserved.
    Keywords:  astrocyte; ischemia; neocortex; neurone; sodium homeostasis
    DOI:  https://doi.org/10.1113/JP284430
  13. Aging Dis. 2023 Mar 27.
    Lipidomic Alterations in the Cerebral Cortex and White Matter in Sporadic Alzheimer's Disease.
    Elia Obis, Joaquim Sol, Pol Andres-Benito, Meritxell Martín-Gari, Natàlia Mota-Martorell, José Daniel Galo-Licona, Gerard Piñol-Ripoll, Manuel Portero-Otin, Isidro Ferrer, Mariona Jové, Reinald Pamplona.
      Non-targeted LC-MS/MS-based lipidomic analysis was conducted in post-mortem human grey matter frontal cortex area 8 (GM) and white matter of the frontal lobe centrum semi-ovale (WM) to identify lipidome fingerprints in middle-aged individuals with no neurofibrillary tangles and senile plaques, and cases at progressive stages of sporadic Alzheimer's disease (sAD). Complementary data were obtained using RT-qPCR and immunohistochemistry. The results showed that WM presents an adaptive lipid phenotype resistant to lipid peroxidation, characterized by a lower fatty acid unsaturation, peroxidizability index, and higher ether lipid content than the GM. Changes in the lipidomic profile are more marked in the WM than in GM in AD with disease progression. Four functional categories are associated with the different lipid classes affected in sAD: membrane structural composition, bioenergetics, antioxidant protection, and bioactive lipids, with deleterious consequences affecting both neurons and glial cells favoring disease progression.
    DOI:  https://doi.org/10.14336/AD.2023.0217
  14. J Neurosci Res. 2023 Apr 26.
    The effect of neuroinflammation on the cerebral metabolism at baseline and after neural stimulation in neurodegenerative diseases.
    Fatima Cheataini, Nissrine Ballout, Tareq Al Sagheer.
      Neuroinflammation is a reaction of nervous tissue to an attack caused by an infection, a toxin, or a neurodegenerative disease. It involves brain metabolism adaptation in order to meet the increased energy needs of glial cell activation, but the nature of these adaptations is still unknown. Increasing interest concerning neuroinflammation leads to the identification of its role in neurodegenerative diseases. Few reports studied the effect of metabolic alteration on neuroinflammation. Metabolic damage initiates a pro-inflammatory response by microglial activation. Moreover, the exact neuroinflammation effect on cerebral cell metabolism remains unknown. In this study, we reviewed systematically the neuroinflammation effect in animal models' brains. All articles showing the relationship of neuroinflammation with brain metabolism, or with neuronal stimulation in neurodegenerative diseases were considered. Moreover, this review examines also the mitochondrial damage effect in neurodegeneration diseases. Then, different biosensors are classified regarding their importance in the determination of metabolite change. Finally, some therapeutic drugs inhibiting neuroinflammation are cited. Neuroinflammation increases lymphocyte infiltration and cytokines' overproduction, altering cellular energy homeostasis. This review demonstrates the importance of neuroinflammation as a mediator of disease progression. Further, the spread of depolarization effects pro-inflammatory genes expression and microglial activation, which contribute to the degeneration of neurons, paving the road to better management and treatment of neurodegenerative diseases.
    Keywords:  cerebral metabolism; mitochondrial dysfunction; neural stimulation; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.1002/jnr.25198
  15. bioRxiv. 2023 May 05. pii: 2023.05.05.539444. [Epub ahead of print]
    Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in Sod1 mutant mouse model of ALS.
    Janice A Dominov, Laura A Madigan, Joshua P Whitt, Katerina L Rademacher, Kristin M Webster, Hesheng Zhang, Haruhiko Banno, Siqi Tang, Yifan Zhang, Nicholas Wightman, Emma M Shychuck, John Page, Alexandra Weiss, Karen Kelly, Alper Kucukural, Michael H Brodsky, Alexander Jaworski, Justin R Fallon, Diane Lipscombe, Robert H Brown.
      Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene ( SOD1 ) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1 G85R protein expression. Heterozygous Sod1 G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1 G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1 G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1 G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1 G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival.SIGNIFICANCE STATEMENT: Amyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying a Sod1 mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar to Sod1 loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenic SOD1 mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.
    DOI:  https://doi.org/10.1101/2023.05.05.539444
  16. J Neurosci. 2023 Apr 21. pii: JN-RM-1494-22. [Epub ahead of print]
    The SphK1/S1P axis regulates synaptic vesicle endocytosis via TRPC5 channels.
    Zhong-Jiao Jiang, Liang-Wei Gong.
      Sphingosine-1-phosphate (S1P), a bioactive sphingolipid concentrated in the brain, is essential for normal brain functions, such as learning and memory and feeding behaviors. Sphingosine kinase 1 (SphK1), the primary kinase responsible for S1P production in the brain, is abundant within presynaptic terminals, indicating a potential role of the SphK1/S1P axis in presynaptic physiology. Altered S1P levels have been highlighted in many neurological diseases with endocytic malfunctions. However, it remains unknown whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis in neurons. The present study evaluates potential functions of the SphK1/S1P axis in synaptic vesicle endocytosis by determining effects of a dominant negative catalytically inactive SphK1. Our data for the first time identify a critical role of the SphK1/S1P axis in endocytosis in both neuroendocrine chromaffin cells and neurons from mice of both sexes. Furthermore, our Ca2+ imaging data indicates that the SphK1/S1P axis may be important for presynaptic Ca2+ increases during prolonged stimulations by regulating the Ca2+ permeable TRPC5 channels, which per se regulate synaptic vesicle endocytosis. Collectively, our data points out a critical role of the regulation of TRPC5 by the SphK1/S1P axis in synaptic vesicle endocytosis.SIGNIFICANCE STATEMENT:Sphingosine kinase 1 (SphK1), the primary kinase responsible for brain sphingosine-1-phosphate (S1P) production, is abundant within presynaptic terminals. Altered SphK1/S1P metabolisms has been highlighted in many neurological disorders with defective synaptic vesicle endocytosis. However, whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis is unknown. Here, we identify that the SphK1/S1P axis regulates the kinetics of synaptic vesicle endocytosis in neurons, in addition to controlling fission-pore duration during single vesicle endocytosis in neuroendocrine chromaffin cells. The regulation of the SphK1/S1P axis in synaptic vesicle endocytosis is specific since it has a distinguished signaling pathway, which involves regulation of Ca2+ influx via TRPC5 channels. This discovery may provide novel mechanistic implications for the SphK1/S1P axis in brain functions under physiological and pathological conditions.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1494-22.2023
  17. Int J Mol Sci. 2023 Apr 29. pii: 8059. [Epub ahead of print]24(9):
    Appraising the Role of Astrocytes as Suppliers of Neuronal Glutathione Precursors.
    Dolores Pérez-Sala, María A Pajares.
      The metabolism and intercellular transfer of glutathione or its precursors may play an important role in cellular defense against oxidative stress, a common hallmark of neurodegeneration. In the 1990s, several studies in the Neurobiology field led to the widely accepted notion that astrocytes produce large amounts of glutathione that serve to feed neurons with precursors for glutathione synthesis. This assumption has important implications for health and disease since a reduction in this supply from astrocytes could compromise the capacity of neurons to cope with oxidative stress. However, at first glance, this shuttling would imply a large energy expenditure to get to the same point in a nearby cell. Thus, are there additional underlying reasons for this expensive mechanism? Are neurons unable to import and/or synthesize the three non-essential amino acids that are the glutathione building blocks? The rather oxidizing extracellular environment favors the presence of cysteine (Cys) as cystine (Cis), less favorable for neuronal import. Therefore, it has also been proposed that astrocytic GSH efflux could induce a change in the redox status of the extracellular space nearby the neurons, locally lowering the Cis/Cys ratio. This astrocytic glutathione release would also increase their demand for precursors, stimulating Cis uptake, which these cells can import, further impacting the local decline of the Cis/Cys ratio, in turn, contributing to a more reduced extracellular environment and subsequently favoring neuronal Cys import. Here, we revisit the experimental evidence that led to the accepted hypothesis of astrocytes acting as suppliers of neuronal glutathione precursors, considering recent data from the Human Protein Atlas. In addition, we highlight some potential drawbacks of this hypothesis, mainly supported by heterogeneous cellular models. Finally, we outline additional and more cost-efficient possibilities by which astrocytes could support neuronal glutathione levels, including its shuttling in extracellular vesicles.
    Keywords:  Alexander disease; amino acid metabolism; amino acid transport; astrocyte and neuron communication; extracellular vesicles; glutathione; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms24098059
  18. Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2301215120
    Impact of acute stress on murine metabolomics and metabolic flux.
    Won Dong Lee, Lingfan Liang, Jenna AbuSalim, Connor S R Jankowski, Laith Z Samarah, Michael D Neinast, Joshua D Rabinowitz.
      Plasma metabolite concentrations and labeling enrichments are common measures of organismal metabolism. In mice, blood is often collected by tail snip sampling. Here, we systematically examined the effect of such sampling, relative to gold-standard sampling from an in-dwelling arterial catheter, on plasma metabolomics and stable isotope tracing. We find marked differences between the arterial and tail circulating metabolome, which arise from two major factors: handling stress and sampling site, whose effects were deconvoluted by taking a second arterial sample immediately after tail snip. Pyruvate and lactate were the most stress-sensitive plasma metabolites, rising ~14 and ~5-fold. Both acute handling stress and adrenergic agonists induce extensive, immediate production of lactate, and modest production of many other circulating metabolites, and we provide a reference set of mouse circulatory turnover fluxes with noninvasive arterial sampling to avoid such artifacts. Even in the absence of stress, lactate remains the highest flux circulating metabolite on a molar basis, and most glucose flux into the TCA cycle in fasted mice flows through circulating lactate. Thus, lactate is both a central player in unstressed mammalian metabolism and strongly produced in response to acute stress.
    Keywords:  catecholamine; in vivo; isotope tracing; metabolomics; stress
    DOI:  https://doi.org/10.1073/pnas.2301215120
  19. Neuro Endocrinol Lett. 2023 Apr 30. 44(2): 101-104
    Niemann-Pick type C disease: Case report and review of the literature.
    Chang Liu, Jiamin Li, Tao Xu, Min Song, Haiyan Luo.
      Niemann-Pick type C (NPC) disease is an autosomal recessive disease of lysosomal lipid storage disorder caused by mutations in either the NPC1 (95%) or the NPC2 (5%) gene. We report a case of a 23-year-old woman who initially showed ataxia, altered gait and tremor. She subsequently developed cognitive decline and psychiatric symptoms. She had asphyxia at birth and was diagnosed as hypoxic-ischemic encephalopathy and cerebral palsy before. The chest computed tomography (CT) incidentally showed splenomegaly. Brain magnetic resonance imaging (MRI) showed no significant abnormalities. Genetic analysis revealed compound heterozygous mutations of NPC1. The clinical picture of NPC can be markedly variable, so comprehensive clinical evaluation, neurological examination and laboratory test are quite important for the diagnosis of NPC.
  20. Int J Mol Sci. 2023 Apr 28. pii: 8042. [Epub ahead of print]24(9):
    Metabolic Disturbance of High-Saturated Fatty Acid Diet in Cognitive Preservation.
    Antonio Rivas-Domínguez, Himan Mohamed-Mohamed, Margarita Jimenez-Palomares, Victoria García-Morales, Laura Martinez-Lopez, Manuel Luis Orta, Juan José Ramos-Rodriguez, Beatriz Bermudez-Pulgarin.
      Aging continues to be the main cause of the development of Alzheimer's, although it has been described that certain chronic inflammatory pathologies can negatively influence the progress of dementia, including obesity and hyperlipidemia. In this sense, previous studies have shown a relationship between low-density lipoprotein receptor (LDLR) and the amyloid-beta (Aβ) binding activity, one of the main neuropathological features of Alzheimer's disease (AD). LDLR is involved in several processes, including lipid transport, regulation of inflammatory response and lipid metabolism. From this perspective, LDLR-/- mice are a widely accepted animal model for the study of pathologies associated with alterations in lipid metabolism, such as familial hypercholesterolemia, cardiovascular diseases, metabolic syndrome, or early cognitive decline. In this context, we induced hyperlipidemia in LDLR-/- mice after feeding with a high-saturated fatty acid diet (HFD) for 44 weeks. LDLR-/--HFD mice exhibited obesity, hypertriglyceridemia, higher glucose levels, and early hepatic steatosis. In addition, HFD increased plasmatic APOE and ubiquitin 60S levels. These proteins are related to neuronal integrity and health maintenance. In agreement, we detected mild cognitive dysfunctions in mice fed with HFD, whereas LDLR-/--HFD mice showed a more severe and evident affectation. Our data suggest central nervous system dysfunction is associated with a well-established metabolic syndrome. As a late consequence, metabolic syndrome boots many behavioral and pathological alterations recognized in dementia, supporting that the control of metabolic parameters could improve cognitive preservation and prognosis.
    Keywords:  HFD; LDL; LDLR; cognition; dementia; episodic memory hyperlipidemia; insulin resistance; saturated fatty acid
    DOI:  https://doi.org/10.3390/ijms24098042
  21. Aging Dis. 2023 Mar 14.
    Neuronal Senescence in the Aged Brain.
    Shu-Min Chou, Yu-Hsin Yen, Fang Yuan, Su-Chun Zhang, Cheong-Meng Chong.
      Cellular senescence is a highly complicated cellular state that occurs throughout the lifespan of an organism. It has been well-defined in mitotic cells by various senescent features. Neurons are long-lived post-mitotic cells with special structures and functions. With age, neurons display morphological and functional changes, accompanying alterations in proteostasis, redox balance, and Ca2+ dynamics; however, it is ambiguous whether these neuronal changes belong to the features of neuronal senescence. In this review, we strive to identify and classify changes that are relatively specific to neurons in the aging brain and define them as features of neuronal senescence through comparisons with common senescent features. We also associate them with the functional decline of multiple cellular homeostasis systems, proposing the possibility that these systems are the main drivers of neuronal senescence. We hope this summary will serve as a steppingstone for further inputs on a comprehensive but relatively specific list of phenotypes for neuronal senescence and in particular their underlying molecular events during aging. This will in turn shine light on the association between neuronal senescence and neurodegeneration and lead to the development of strategies to perturb the processes.
    DOI:  https://doi.org/10.14336/AD.2023.0214
  22. Biomolecules. 2023 Apr 20. pii: 695. [Epub ahead of print]13(4):
    Connecting Dots between Mitochondrial Dysfunction and Depression.
    Mehtab Khan, Yann Baussan, Etienne Hebert-Chatelain.
      Mitochondria are the prime source of cellular energy, and are also responsible for important processes such as oxidative stress, apoptosis and Ca2+ homeostasis. Depression is a psychiatric disease characterized by alteration in the metabolism, neurotransmission and neuroplasticity. In this manuscript, we summarize the recent evidence linking mitochondrial dysfunction to the pathophysiology of depression. Impaired expression of mitochondria-related genes, damage to mitochondrial membrane proteins and lipids, disruption of the electron transport chain, higher oxidative stress, neuroinflammation and apoptosis are all observed in preclinical models of depression and most of these parameters can be altered in the brain of patients with depression. A deeper knowledge of the depression pathophysiology and the identification of phenotypes and biomarkers with respect to mitochondrial dysfunction are needed to help early diagnosis and the development of new treatment strategies for this devastating disorder.
    Keywords:  ATP; OXPHOS; depression; mitochondria
    DOI:  https://doi.org/10.3390/biom13040695
  23. Stem Cell Reports. 2023 Apr 29. pii: S2213-6711(23)00141-8. [Epub ahead of print]
    Regulation of neural stem cell differentiation and brain development by MGAT5-mediated N-glycosylation.
    Andrew R Yale, Estelle Kim, Brenda Gutierrez, J Nicole Hanamoto, Nicole S Lav, Jamison L Nourse, Marc Salvatus, Robert F Hunt, Edwin S Monuki, Lisa A Flanagan.
      Undifferentiated neural stem and progenitor cells (NSPCs) encounter extracellular signals that bind plasma membrane proteins and influence differentiation. Membrane proteins are regulated by N-linked glycosylation, making it possible that glycosylation plays a critical role in cell differentiation. We assessed enzymes that control N-glycosylation in NSPCs and found that loss of the enzyme responsible for generating β1,6-branched N-glycans, N-acetylglucosaminyltransferase V (MGAT5), led to specific changes in NSPC differentiation in vitro and in vivo. Mgat5 homozygous null NSPCs in culture formed more neurons and fewer astrocytes compared with wild-type controls. In the brain cerebral cortex, loss of MGAT5 caused accelerated neuronal differentiation. Rapid neuronal differentiation led to depletion of cells in the NSPC niche, resulting in a shift in cortical neuron layers in Mgat5 null mice. Glycosylation enzyme MGAT5 plays a critical and previously unrecognized role in cell differentiation and early brain development.
    Keywords:  MGAT5; N-glycan branching; astrocyte; brain; cerebral cortex; glycosylation; neural stem cell; neuron
    DOI:  https://doi.org/10.1016/j.stemcr.2023.04.007
  24. J Alzheimers Dis. 2023 May 05.
    Accelerated Breakdown of Phosphatidylcholine and Phosphatidylethanolamine Is a Predominant Brain Metabolic Defect in Alzheimer's Disease.
    Jan Krzysztof Blusztajn, Barbara E Slack.
      Numerous studies have demonstrated defects in multiple metabolic pathways in Alzheimer's disease (AD), detected in autopsy brains and in the cerebrospinal fluid in vivo. However, until the advent of techniques capable of measuring thousands of metabolites in a single sample, it has not been possible to rank the relative magnitude of these abnormalities. A recent study provides evidence that the abnormal turnover of the brain's most abundant phospholipids: phosphatidylcholine and phosphatidylethanolamine, constitutes a major metabolic pathology in AD. We place this observation in a historical context and discuss the implications of a central role for phospholipid metabolism in AD pathogenesis.
    Keywords:  Alzheimer’s disease; glycerophosphocholine; glycerophosphoethanolamine; lipidomics; metabolome; metabolomics; phosphatidylcholine; phosphatidylethanolamine
    DOI:  https://doi.org/10.3233/JAD-230061
  25. Cell Calcium. 2023 May 11. pii: S0143-4160(23)00069-6. [Epub ahead of print]113 102757
    Mitochondrial Ca2+ signaling and Alzheimer's disease: Too much or too little?
    Paloma Garcia-Casas, Michela Rossini, Riccardo Filadi, Paola Pizzo.
      Alzheimer's disease (AD) is a neurodegenerative disease, caused by poorly known pathogenic mechanisms and aggravated by delayed therapeutic intervention, that still lacks an effective cure. However, it is clear that some important neurophysiological processes are altered years before the onset of clinical symptoms, offering the possibility of identifying biological targets useful for implementation of new therapies. Of note, evidence has been provided suggesting that mitochondria, pivotal organelles in sustaining neuronal energy demand and modulating synaptic activity, are dysfunctional in AD samples. In particular, alterations in mitochondrial Ca2+ signaling have been proposed as causal events for neurodegeneration, although the exact outcomes and molecular mechanisms of these defects, as well as their longitudinal progression, are not always clear. Here, we discuss the importance of a correct mitochondrial Ca2+ handling for neuronal physiology and summarize the latest findings on dysfunctional mitochondrial Ca2+ pathways in AD, analysing possible consequences contributing to the neurodegeneration that characterizes the disease.
    Keywords:  Alzheimer's disease; ER-mitochondria contacts; MCU; Mitochondrial calcium signaling; NCLX; Presenilin
    DOI:  https://doi.org/10.1016/j.ceca.2023.102757
  26. Nat Cardiovasc Res. 2022 ;1(3): 238-245
    Cholesterol efflux mechanism revealed by structural analysis of human ABCA1 conformational states.
    Yingyuan Sun, Xiaochun Li.
      ATP-binding cassette transporter A1 (ABCA1) utilizes energy derived from ATP hydrolysis to export cholesterol and phospholipids from macrophages. ABCA1 plays a central role in the biosynthesis of high-density lipoprotein (HDL), which mediates reverse cholesterol transport and prevents detrimental lipid deposition. Mutations in ABCA1 cause Tangier disease characterized by a remarkable reduction in the amount of HDL in blood. Here we present cryo-electron microscopy structures of human ABCA1 in ATP-bound and nucleotide-free states. Structural comparison reveals that ATP molecules pull the nucleotide-binding domains together, inducing movements of transmembrane helices 1, 2, 7 and 8 through a series of salt-bridge interactions. Subsequently, extracellular domains (ECDs) undergo a rotation and introduce conformational changes in the ECD-transmembrane interface. In addition, while we observe a sterol-like molecule in ECDs, no such density was observed in the structure of an HDL-deficiency mutant ABCA1Y482C, demonstrating the physiological importance of ECDs and a putative interaction mode between ABCA1 and its lipid acceptors. Thus, these structures, along with cholesterol efflux assays, advance the understanding ABCA1-mediated reverse cholesterol transport.
    DOI:  https://doi.org/10.1038/s44161-022-00022-y
  27. Mult Scler. 2023 May 18. 13524585231171517
    Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis.
    Akash Virupakshaiah, Dimitrios C Ladakis, Bardia Nourbakhsh, Pavan Bhargava, Sonam Dilwali, Vinicius Schoeps, Kamil Borkowski, John W Newman, Emmanuelle Waubant.
      BACKGROUND: The circulating metabolome is altered in multiple sclerosis (MS), but its prognostic capabilities have not been extensively explored. Lipid metabolites might be of particular interest due to their multiple roles in the brain, as they can serve as structural components, energy sources, and bioactive molecules. Gaining a deeper understanding of the disease may be possible by examining the lipid metabolism in the periphery, which serves as the primary source of lipids for the brain.OBJECTIVE: To determine if altered serum lipid metabolites are associated with the risk of relapse and disability in children with MS.
    METHODS: We collected serum samples from 61 participants with pediatric-onset MS within 4 years of disease onset. Prospective longitudinal relapse data and cross-sectional disability measures (Expanded Disability Status Scale (EDSS)) were collected. Serum metabolomics was performed using untargeted liquid chromatography and mass spectrometry. Individual lipid metabolites were clustered into pre-defined pathways. The associations between clusters of metabolites and relapse rate and EDSS score were estimated utilizing negative binomial and linear regression models, respectively.
    RESULTS: We found that serum acylcarnitines (relapse rate: normalized enrichment score (NES) = 2.1, q = 1.03E-04; EDSS: NES = 1.7, q = 0.02) and poly-unsaturated fatty acids (relapse rate: NES = 1.6, q = 0.047; EDSS: NES = 1.9, q = 0.005) were associated with higher relapse rates and EDSS, while serum phosphatidylethanolamines (relapse rate: NES = -2.3, q = 0.002; EDSS: NES = -2.1, q = 0.004), plasmalogens (relapse rate: NES = -2.5, q = 5.81E-04; EDSS: NES = -2.1, q = 0.004), and primary bile acid metabolites (relapse rate: NES = -2.0, q = 0.02; EDSS: NES = -1.9, q = 0.02) were associated with lower relapse rates and lower EDSS.
    CONCLUSION: This study supports the role of some lipid metabolites in pediatric MS relapses and disability.
    Keywords:  EDSS; Pediatric onset MS; lipidomics; relapse rate
    DOI:  https://doi.org/10.1177/13524585231171517
  28. Adv Sci (Weinh). 2023 May 18. e2300758
    Ameliorating Mitochondrial Dysfunction of Neurons by Biomimetic Targeting Nanoparticles Mediated Mitochondrial Biogenesis to Boost the Therapy of Parkinson's Disease.
    Qing Zheng, Hanghang Liu, Hao Zhang, Yaobao Han, Jiaxin Yuan, Tingting Wang, Yifan Gao, Zhen Li.
      Mitochondrial dysfunction of neurons is the core pathogenesis of incurable Parkinson's disease (PD). It is crucial to ameliorate the mitochondrial dysfunction of neurons for boosting the therapy of PD. Herein, the remarkable promotion of mitochondrial biogenesis to ameliorate mitochondrial dysfunction of neurons and improve the treatment of PD by using mitochondria-targeted biomimetic nanoparticles, which are Cu2- x Se-based nanoparticles functionalized with curcumin and wrapped with DSPE-PEG2000 -TPP-modified macrophage membrane (denoted as CSCCT NPs), is reported. These nanoparticles can efficiently target mitochondria of damaged neurons in an inflammatory environment, and mediate the signaling pathway of NAD+ /SIRT1/PGC-1α/PPARγ/NRF1/TFAM to alleviate 1-methyl-4-phenylpyridinium (MPP+ )-induced neuronal toxicity. They can reduce the mitochondrial reactive oxygen species, restore mitochondrial membrane potential (MMP), protect the integrity of mitochondrial respiratory chain, and ameliorate mitochondrial dysfunction via promoting mitochondrial biogenesis, which synergistically improve the motor disorders and anxiety behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. This study demonstrates that targeting mitochondrial biogenesis to ameliorate mitochondrial dysfunction has a great potential in the treatment of PD and mitochondria-related diseases.
    Keywords:  Parkinson's disease; SIRT1/PGC-1α pathway; biomimetic nanoparticles; mitochondrial biogenesis; mitochondrial dysfunction
    DOI:  https://doi.org/10.1002/advs.202300758
  29. Int J Biol Macromol. 2023 May 13. pii: S0141-8130(23)01753-1. [Epub ahead of print]242(Pt 2): 124859
    Role of de novo lipogenesis in inflammation and insulin resistance in alzheimer's disease.
    Mohsin Ali Khan, Zaw Ali Khan, Fouzia Shoeb, Ghizal Fatima, Rizwan Hasan Khan, Mohammad M Khan.
      Patients with Alzheimer's disease (AD) display both peripheral tissue and brain insulin resistance, the later could be a potential risk factor for cognitive dysfunction. While certain degree of inflammation is required for inducing insulin resistance, underlying mechanism(s) remains unclear. Evidence from diverse research domains suggest that elevated intracellular fatty acids of de novo pathway can induce insulin resistance even without triggering inflammation; however, the effect of saturated fatty acids (SFAs) could be detrimental due the development of proinflammatory cues. In this context, evidence suggest that while lipid/fatty acid accumulation is a characteristic feature of brain pathology in AD, dysregulated de novo lipogenesis could be a potential source for lipid/fatty acid accumulation. Therefore, therapies aimed at regulating de novo lipogenesis could be effective in improving insulin sensitivity and cognitive function in patients with AD.
    Keywords:  Alzheimer's disease; Cognitive dysfunction; Inflammation; Insulin resistance; de novo lipogenesis
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.124859
  30. J Neurosci. 2023 May 17. pii: JN-RM-2312-22. [Epub ahead of print]
    Elevated galectin-3 is associated with aging, multiple sclerosis, and oxidized phosphatidylcholine induced neurodegeneration.
    Sara Xue, Brian M Lozinski, Samira Ghorbani, Khanh Ta, Charlotte D'Mello, V Wee Yong, Yifei Dong.
      Aging is a significant risk factor associated with the progression of central nervous system (CNS) neurodegenerative diseases including multiple sclerosis (MS). Microglia, the resident macrophages of the CNS parenchyma, are a major population of immune cells that accumulate in MS lesions. While they normally regulate tissue homeostasis and facilitate the clearance of neurotoxic molecules including oxidized phosphatidylcholines (OxPC), their transcriptome and neuroprotective functions are reprogrammed by aging. Thus, determining the factors that instigate aging associated microglia dysfunction can lead to new insights for promoting CNS repair and for halting MS disease progression. Through single cell RNA sequencing, we identified Lgals3, which encodes for galectin-3 (Gal3), as an age upregulated gene by microglia responding to OxPC. Consistently, excess Gal3 accumulated in OxPC and lysolecithin induced focal spinal cord white matter lesions of middle-aged mice compared to young mice. Gal3 was also elevated in mouse experimental autoimmune encephalomyelitis lesions and more importantly in MS brain lesions from 2 male and 1 female individuals. While Gal3 delivery alone into the mouse spinal cord did not induce damage, its co-delivery with OxPC increased cleaved caspase 3 and IL-1β within white matter lesions and exacerbated OxPC induced injury. Conversely, OxPC mediated neurodegeneration was reduced in Gal3-/- mice compared to Gal3+/+ mice. Thus, Gal3 is associated with increased neuroinflammation and neurodegeneration and its overexpression by microglia/macrophages may be detrimental for lesions within the aging CNS.SIGNIFICANCE STATEMENT:Aging accelerates the progression of neurodegenerative diseases such as multiple sclerosis (MS). Understanding the molecular mechanisms of aging that increases the susceptibility of the central nervous system (CNS) to damage could lead to new strategies to manage MS progression. Here, we highlight that microglia/macrophage associated galectin-3 (Gal3) was upregulated with age exacerbated neurodegeneration in the mouse spinal cord white matter and in MS lesions. More importantly, co-injection of Gal3 with oxidized phosphatidylcholines (OxPC), which are neurotoxic lipids found in MS lesions, caused greater neurodegeneration compared to injection of OxPC alone, whereas genetic loss of Gal3 reduced OxPC damage. These results demonstrate that Gal3 overexpression is detrimental to CNS lesions and suggest its deposition in MS lesions may contribute to neurodegeneration.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2312-22.2023
  31. Int J Mol Sci. 2023 May 07. pii: 8398. [Epub ahead of print]24(9):
    Systemic Metabolism and Mitochondria in the Mechanism of Alzheimer's Disease: Finding Potential Therapeutic Targets.
    Meiying Song, Xiang Fan.
      Elderly people over the age of 65 are those most likely to experience Alzheimer's disease (AD), and aging and AD are associated with apparent metabolic alterations. Currently, there is no curative medication against AD and only several drugs have been approved by the FDA, but these drugs can only improve the symptoms of AD. Many preclinical and clinical trials have explored the impact of adjusting the whole-body and intracellular metabolism on the pathogenesis of AD. The most recent evidence suggests that mitochondria initiate an integrated stress response to environmental stress, which is beneficial for healthy aging and neuroprotection. There is also an increasing awareness of the differential risk and potential targeting strategies related to the metabolic level and microbiome. As the main participants in intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been regarded as potential therapeutic targets for AD. This review summarizes and highlights these advances.
    Keywords:  Alzheimer’s disease; glucose metabolism; gut–brain axis; insulin signaling; metal metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms24098398
  32. Elife. 2023 May 19. pii: e82683. [Epub ahead of print]12
    Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain.
    Federico Salas-Lucia, Csaba Fekete, Richárd Sinko, Péter Egri, Kristóf Rada, Yvette Ruska, Balázs Gereben, Antonio Bianco.
      The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.
    Keywords:  medicine; mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.82683
  33. Neurochem Res. 2023 May 13.
    The Regulation of GLT-1 Degradation Pathway by SIRT4.
    Emre Yeşilören, Gizem Donmez Yalcin.
      Glial cells give rise to glioblastoma multiform as a primary brain tumor. In glioblastomas, neurons are destroyed via excitotoxicity which is the accumulation of excess glutamate in synaptic cavity. Glutamate Transporter 1 (GLT-1) is the main transporter that absorbs the excessive glutamate. Sirtuin 4 (SIRT4) was shown to have a potential protective role against excitotoxicity in previous studies. In this study, the regulation of dynamic GLT-1 expression by SIRT4 was analyzed in glia (immortalized human astrocytes) and glioblastoma (U87) cells. The expression of GLT-1 dimers and trimers were reduced and the ubiquitination of GLT-1 was increased in glioblastoma cells when SIRT4 was silenced; however GLT-1 monomer was not affected. In glia cells, SIRT4 reduction did not affect GLT-1 monomer, dimer, trimer expression or the ubiquitination of GLT-1. The phosphorylation of Nedd4-2 and the expression of PKC did not change in glioblastoma cells when SIRT4 was silenced but increased in glia cells. We also showed that SIRT4 deacetylates PKC in glia cells. In addition, GLT-1 was shown to be deacetylated by SIRT4 which might be a priority for ubiquitination. Therefore, we conclude that GLT-1 expression is regulated differently in glia and glioblastoma cells. SIRT4 activators or inhibitors of ubiquitination may be used to prevent excitotoxicity in glioblastomas.
    Keywords:  GLT-1; Glioblastoma; Nedd4-2; SIRT4; Ubiquitin
    DOI:  https://doi.org/10.1007/s11064-023-03947-3
  34. Aging Dis. 2023 Mar 31.
    Changes in Plasma Neutral and Ether-Linked Lipids Are Associated with The Pathology and Progression of Alzheimer's Disease.
    Farida Dakterzada, Mariona Jové, Raquel Huerto, Anna Carnes, Joaquim Sol, Reinald Pamplona, Gerard Piñol-Ripoll.
      Aberrant lipid metabolism has been strongly linked to Alzheimer's disease (AD) pathogenesis. However, the role of lipids in the pathophysiological processes of AD and their clinical progression is unclear. We hypothesized that plasma lipids are associated with the pathological hallmarks of AD, progression from mild cognitive impairment (MCI) to AD, and the rate of cognitive decline in MCI patients. To evaluate our hypotheses, we analysed the plasma lipidome profile by liquid chromatography coupled to mass spectrometry in an LC-ESI-QTOF-MS/MS platform for 213 subjects recruited consecutively: 104 AD, 89 MCI, and 20 control subjects. Forty-seven (52.8%) MCI patients progressed to AD during follow-up (58 ± 12.5 months). We found that higher plasma levels of sphingomyelin SM(36:0) and diglyceride DG(44:3) were associated with an increased risk of amyloid beta 42 (Aβ42) positivity in CSF, while levels of SM(40:1) were associated with a reduced risk. Higher plasma levels of ether-linked triglyceride TG(O-60:10) were negatively associated with pathological levels of phosphorylated tau in CSF. Plasma levels of fatty acid ester of hydroxy fatty acid FAHFA(34:0) and ether-linked phosphatidylcholine PC(O-36:1) were positively associated with pathological levels of total tau in CSF. Regarding the plasma lipids most associated with progression from MCI to AD, our analysis detected phosphatidyl-ethanolamine plasmalogen PE(P-36:4), TG(59:12), TG(46:0), and TG(O-62:7). Furthermore, TG(O-62:7) was the lipid that was most strongly associated with the rate of progression. In conclusion, our results indicate that neutral and ether-linked lipids are involved in the pathophysiological processes of AD and the progression from MCI to AD dementia, suggesting the involvement of lipid-mediated antioxidant mechanisms in AD.
    DOI:  https://doi.org/10.14336/AD.2023.0221
  35. J Biol Chem. 2023 May 10. pii: S0021-9258(23)01830-6. [Epub ahead of print] 104802
    Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners.
    Yidan Xu, Joji Kusuyama, Shion Osana, Satayuki Matsuhashi, Longfei Li, Hiroaki Takada, Hitoshi Inada, Ryoichi Nagatomi.
      Lactate serves as the major glucose alternative to an energy substrate in the brain. Lactate level is increased in the fetal brain from the middle stage of gestation, indicating the involvement of lactate in brain development and neuronal differentiation. Recent reports show that lactate functions as a signaling molecule to regulate gene expression and protein stability. However, the roles of lactate signaling in neuronal cells remain unknown. Here, we showed that lactate promotes the all stages of neuronal differentiation of SH-SY5Y and Neuro2A, human and mouse neuroblastoma cell lines, characterized by increased neuronal marker expression and the rates of neurites extension. Transcriptomics revealed many lactate-responsive genes sets such as SPARCL1 in SH-SY5Y, Neuro2A, and primary embryonic mouse neuronal cells. The effects of lactate on neuronal function were mainly mediated through monocarboxylate transporters 1 (MCT1). We found that NDRG family member 3 (NDRG3), a lactate-binding protein, was highly expressed and stabilized by lactate treatment during neuronal differentiation. Combinative RNA-seq of SH-SY5Y with lactate treatment and NDRG3 knockdown shows that the promotive effects of lactate on neural differentiation are regulated through NDRG3-dependent and independent manners. Moreover, we identified TEA domain family member 1 (TEAD1) and ETS-related transcription factor 4 (ELF4) are the specific transcription factors that are regulated by both lactate and NDRG3 in neuronal differentiation. TEAD1 and ELF4 differently affect the expression of neuronal marker genes in SH-SY5Y cells. These results highlight the biological roles of extracellular and intracellular lactate as a critical signaling molecule that modifies neuronal differentiation.
    Keywords:  GPR81; ID2; MAP2; NF-H; NSE; RUNX1T1; SYT4; TUBB3; neurogenesis
    DOI:  https://doi.org/10.1016/j.jbc.2023.104802
  36. Exp Biol Med (Maywood). 2023 May 19. 15353702231165010
    Alpha-linolenic acid enhances the facilitation of GABAergic neurotransmission in the BLA and CA1.
    Volodymir I Pidoplichko, Taiza H Figueiredo, Maria Fm Braga, Hongna Pan, Ann M Marini.
      Hyperexcitability is a major mechanism implicated in several neuropsychiatric disorders, such as organophosphate-induced status epilepticus (SE), primary epilepsy, stroke, spinal cord injury, traumatic brain injury, schizophrenia, and autism spectrum disorders. Underlying mechanisms are diverse, but a functional impairment and loss of GABAergic inhibitory neurons are common features in many of these disorders. While novel therapies abound to correct for the loss of GABAergic inhibitory neurons, it has been difficult at best to improve the activities of daily living for the majority of patients. Alpha-linolenic acid (ALA) is an essential omega-3 polyunsaturated fatty acid found in plants. ALA exerts pleiotropic effects in the brain that attenuate injury in chronic and acute brain disease models. However, the effect of ALA on GABAergic neurotransmission in hyperexcitable brain regions involved in neuropsychiatric disorders, such as the basolateral amygdala (BLA) and CA1 subfield of the hippocampus, is unknown. Administration of a single dose of ALA (1500 nmol/kg) subcutaneously increased the charge transfer of inhibitory postsynaptic potential currents mediated by GABAA receptors in pyramidal neurons by 52% in the BLA and by 92% in the CA1 compared to vehicle animals a day later. Similar results were obtained in pyramidal neurons from the BLA and CA1 when ALA was bath-applied in slices from naïve animals. Importantly, pretreatment with the high-affinity, selective TrkB inhibitor, k252, completely abolished the ALA-induced increase in GABAergic neurotransmission in the BLA and CA1, suggesting a brain-derived neurotrophic factor (BDNF)-mediated mechanism. Addition of mature BDNF (20 ng/mL) significantly increased GABAA receptor inhibitory activity in the BLA and CA1 pyramidal neurons similar to the results obtained with ALA. ALA may be an effective treatment for neuropsychiatric disorders where hyperexcitability is a major feature.
    Keywords:  GABAA receptors; Rat; alpha-linolenic acid; brain-derived neurotrophic factor; hyperexcitability; neurons; omega-3 polyunsaturated fatty acids
    DOI:  https://doi.org/10.1177/15353702231165010
  37. Int J Mol Sci. 2023 Apr 22. pii: 7682. [Epub ahead of print]24(9):
    N-Acetylaspartate and Choline Metabolites in Cortical and Subcortical Regions in Clinical High Risk Relative to Healthy Control Subjects: An Exploratory 7T MRSI Study.
    Ahmad Mayeli, Sabine A Janssen, Chloe A Huston, Julia S Rupp, Kamakashi Sharma, Chan-Hong Moon, Ahmadreza Keihani, Hoby P Hetherington, Fabio Ferrarelli.
      N-acetylaspartate (NAA) and choline (Cho) are two brain metabolites implicated in several key neuronal functions. Abnormalities in these metabolites have been reported in both early course and chronic patients with schizophrenia (SCZ). It is, however, unclear whether NAA and Cho's alterations occur even before the onset of the disorder. Clinical high risk (CHR) individuals are a population uniquely enriched for psychosis and SCZ. In this exploratory study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to examine differences in total NAA (tNAA; NAA + N-acetylaspartylglutamate [NAAG]) and major choline-containing compounds, including glycerophosphorylcholine and phosphorylcholine [tCho], over the creatine (Cre) levels between 26 CHR and 32 healthy control (HC) subjects in the subcortical and cortical regions. While no tCho/Cre differences were found between groups in any of the regions of interest (ROIs), we found that CHR had significantly reduced tNAA/Cre in the right dorsal lateral prefrontal cortex (DLPFC) compared to HC, and that the right DLPFC tNAA/Cre reduction in CHR was negatively associated with their positive symptoms scores. No tNAA/Cre differences were found between CHR and HC in other ROIs. In conclusion, reduced tNAA/Cre in CHR vs. HC may represent a putative molecular biomarker for risk of psychosis and SCZ that is associated with symptom severity.
    Keywords:  DLPFC; NAA; brain cortical regions; choline; clinical high risk for psychosis
    DOI:  https://doi.org/10.3390/ijms24097682
  38. Mol Metab. 2023 May 13. pii: S2212-8778(23)00072-8. [Epub ahead of print] 101738
    The local GLP-1 system in the olfactory bulb is required for odor-evoked cephalic phase of insulin release in mice.
    Mireia Montaner, Jessica Denom, Wanqing Jiang, Christophe Magnan, Stefan Trapp, Hirac Gurden.
      OBJECTIVE: The olfactory bulb (OB) codes for sensory information and contributes to the control of energy metabolism by regulating foraging and cephalic phase responses. Mitral cells are the main output neurons of the OB. The Glucagon Like Peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) system in the OB (GLP-1OB) has been shown to be a major regulator of mitral cell activity but its function in vivo is unclear. Therefore, we investigated the role of GLP-1OB in foraging behavior and odor-evoked Cephalic Phase Insulin Release (CPIR).METHODS AND RESULTS: By fluorescent labeling, we confirmed the presence of GLP-1 producing neurons and the expression of GLP-1R in the mouse OB. In response to food odor presentation, we collected blood, quantified plasma insulin by ELISA and showed the existence of an odor-evoked CPIR in lean mice but its absence in obese animals. Injection of shRNA against preproglucagon mRNA in the OB resulted in blunted CPIR in lean mice. Injecting Exendin (9-39), a GLP-1R antagonist, into the OB of lean mice also resulted in decreased CPIR. Since parasympathetic cholinergic input to the pancreas is known to be partly responsible for CPIR, we systemically administered the muscarinic M3 receptor antagonist 4-DAMP which resulted in a reduced odor-evoked CPIR. Finally, local injection of Exendin (9-39) in the OB extinguished olfactory foraging in lean mice whereas the injection of the GLP-1R agonist Exendin-4 rescued the loss of foraging behavior in obese mice.
    CONCLUSIONS: Our results demonstrate that GLP-1OB controls olfactory foraging and is required for odor-evoked CPIR. We describe a new crucial brain function for GLP-1 and GLP-1R expressed within the brain.
    Keywords:  Cephalic phase insulin release; Foraging; Glucagon like Peptide-1; M3 muscarinic receptors; Obesity; Olfactory bulb
    DOI:  https://doi.org/10.1016/j.molmet.2023.101738
  39. Annu Rev Nutr. 2023 May 19.
    The Multifunctional Family of Mammalian Fatty Acid-Binding Proteins.
    Judith Storch, Betina Corsico.
      Fatty acid-binding proteins (FABPs) are small lipid-binding proteins abundantly expressed in tissues that are highly active in fatty acid (FA) metabolism. Ten mammalian FABPs have been identified, with tissue-specific expression patterns and highly conserved tertiary structures. FABPs were initially studied as intracellular FA transport proteins. Further investigation has demonstrated their participation in lipid metabolism, both directly and via regulation of gene expression, and in signaling within their cells of expression. There is also evidence that they may be secreted and have functional impact via the circulation. It has also been shown that the FABP ligand binding repertoire extends beyond long-chain FAs and that their functional properties also involve participation in systemic metabolism. This article reviews the present understanding of FABP functions and their apparent roles in disease, particularly metabolic and inflammation-related disorders and cancers. Expected final online publication date for the Annual Review of Nutrition, Volume 43 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-nutr-062220-112240
  40. Neurology. 2023 05 16. 100(20): 970-977
    What Are the Roles of Pericytes in the Neurovascular Unit and Its Disorders?
    Eduardo Benarroch.
      
    DOI:  https://doi.org/10.1212/WNL.0000000000207379
  41. Molecules. 2023 Apr 29. pii: 3810. [Epub ahead of print]28(9):
    Anticonvulsant Profile of Selected Medium-Chain Fatty Acids (MCFAs) Co-Administered with Metformin in Mice in Acute and Chronic Treatment.
    Mateusz Pieróg, Katarzyna Socała, Dorota Nieoczym, Elżbieta Wyska, Małgorzata Samorek-Pieróg, Piotr Wlaź.
      In contrast to the other components of the medium-chain triglycerides ketogenic diet (MCT KD), i.e., caprylic acid (CA8), a comprehensive evaluation of caproic (CA6) and lauric acids' (CA12) properties in standard chemical and electrical seizure tests in mice has not yet been performed. We investigated their effects in maximal electroshock seizure threshold (MEST), 6 Hz seizure threshold and intravenous (i.v.) pentylenetetrazole (PTZ) seizure tests. Since ketone body production can be regulated by the activation of 5'AMP-activated protein kinase (AMPK), we hypothesized that metformin (an AMPK activator) enhance ketogenesis and would act synergistically with the fatty acids to inhibit convulsions. We assessed the effects of acute and chronic co-treatment with metformin and CA6/CA8 on seizures. CA6 and CA12 (p.o.) increased seizure threshold in the 6 Hz seizure test. CA6 at the highest tested dose (30 mmol/kg) developed toxicity in several mice, impaired motor performance and induced ketoacidosis. Acute and chronic co-treatment with metformin and CA6/CA8 did not affect seizure thresholds. Moreover, we observed the pro-convulsive effect of the acute co-administration of CA8 (5 mmol/kg) and metformin (100 mg/kg). Since this co-treatment was pro-convulsive, the safety profile and risk/benefit ratio of MCT KD and metformin concomitant therapy in epileptic patients should be further evaluated.
    Keywords:  6 Hz seizure test; MEST; caproic acid; caprylic acid; lauric acid; metformin; mice; pentylenetetrazole; seizure threshold; seizures
    DOI:  https://doi.org/10.3390/molecules28093810
  42. Proc Natl Acad Sci U S A. 2023 05 23. 120(21): e2220684120
    Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model.
    Wenqiang Chen, Qian Huang, Ekaterina Katie Lazdon, Antonio Gomes, Marisa Wong, Emily Stephens, Tabitha Grace Royal, Dan Frenkel, Weikang Cai, C Ronald Kahn.
      Brain insulin signaling controls peripheral energy metabolism and plays a key role in the regulation of mood and cognition. Epidemiological studies have indicated a strong connection between type 2 diabetes (T2D) and neurodegenerative disorders, especially Alzheimer's disease (AD), linked via dysregulation of insulin signaling, i.e., insulin resistance. While most studies have focused on neurons, here, we aim to understand the role of insulin signaling in astrocytes, a glial cell type highly implicated in AD pathology and AD progression. To this end, we created a mouse model by crossing 5xFAD transgenic mice, a well-recognized AD mouse model that expresses five familial AD mutations, with mice carrying a selective, inducible insulin receptor (IR) knockout in astrocytes (iGIRKO). We show that by age 6 mo, iGIRKO/5xFAD mice exhibited greater alterations in nesting, Y-maze performance, and fear response than those of mice with the 5xFAD transgenes alone. This was associated with increased Tau (T231) phosphorylation, increased Aβ plaque size, and increased association of astrocytes with plaques in the cerebral cortex as assessed using tissue CLARITY of the brain in the iGIRKO/5xFAD mice. Mechanistically, in vitro knockout of IR in primary astrocytes resulted in loss of insulin signaling, reduced ATP production and glycolic capacity, and impaired Aβ uptake both in the basal and insulin-stimulated states. Thus, insulin signaling in astrocytes plays an important role in the control of Aβ uptake, thereby contributing to AD pathology, and highlighting the potential importance of targeting insulin signaling in astrocytes as a site for therapeutics for patients with T2D and AD.
    Keywords:  Alzheimer’s disease; astrocytes; diabetes; insulin resistance; neurons
    DOI:  https://doi.org/10.1073/pnas.2220684120
  43. Biomedicines. 2023 Mar 26. pii: 1011. [Epub ahead of print]11(4):
    The Effects of PP2A Disruption on ER-Mitochondria Contact and Mitochondrial Functions in Neuronal-like Cells.
    Phaewa Chaiwijit, Kwanchanok Uppakara, Nithi Asavapanumas, Witchuda Saengsawang.
      Mitochondria-associated membranes (MAMs) regulate several cellular processes, including calcium homeostasis and mitochondrial function, and dynamics. While MAMs are upregulated in Alzheimer's disease (AD), the mechanisms underlying this increase remain unknown. A possible mechanism may include dysregulation of protein phosphatase 2A (PP2A), which is reduced in the AD brain. Furthermore, PP2A has been previously reported to modulate MAM formation in hepatocytes. However, it is unknown whether PP2A and MAMs are linked in neuronal cells. Here, to test the correlation between PP2A and MAMs, we inhibited the activity of PP2A to mimic its low levels in AD brains and observed MAM formation, function, and dynamics. MAMs were significantly increased after PP2A inhibition, which correlated with elevated mitochondrial Ca2+ influx and disrupted mitochondrial membrane potential and mitochondrial fission. This study highlights the essential role PP2A plays in regulating MAM formation and mitochondrial function and dynamics for the first time in neuronal-like cells.
    Keywords:  Alzheimer’s disease; ER-mitochondria contacts; MAMs; PP2A; Tau; calcium; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/biomedicines11041011
  44. Mol Genet Metab. 2023 May 09. pii: S1096-7192(23)00235-4. [Epub ahead of print]139(2): 107605
    Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.
    M Laura Duque Lasio, Angela C Leshinski, Nicole H Ducich, Leigh Anne Flore, April Lehman, Natasha Shur, Parul B Jayakar, Bryan E Hainline, Alice A Basinger, William G Wilson, George A Diaz, Richard W Erbe, Dwight D Koeberl, Jerry Vockley, Jirair K Bedoyan.
      Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis. The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction. Use of the anaplerotic agent triheptanoin on a limited number of individuals with PCD has had mixed results. We expand on the potential utility of triheptanoin in PCD by examining the clinical, biochemical, molecular, and health-related quality-of-life (HRQoL) findings in a cohort of 12 individuals with PCD (eight with Type A and two each with Types B and C) treated with triheptanoin ranging for 6 days to about 7 years. The main endpoints were changes in blood lactate and HRQoL scores, but collection of useful data was limited to about half of subjects. An overall trend of lactate reduction with time on triheptanoin was noted, but with significant variability among subjects and only one subject reaching close to statistical significance for this endpoint. Parent reported HRQoL assessments with treatment showed mixed results, with some subjects showing no change, some improvement, and some worsening of overall scores. Subjects with buried amino acids in the pyruvate carboxyltransferase domain of PC that undergo destabilizing replacements may be more likely to respond (with lactate reduction or HRQoL improvement) to triheptanoin compared to those with replacements that disrupt tetramerization or subunit-subunit interface contacts. The reason for this difference is unclear and requires further validation. We observed significant variability but an overall trend of lactate reduction with time on triheptanoin and mixed parent reported outcome changes by HRQoL assessments for subjects with PCD on long-term triheptanoin. The mixed results noted with triheptanoin therapy in this study could be due to endpoint data limitation, variability of disease severity between subjects, limitation of the parent reported HRQoL tool, or subject genotype variability. Alternative designed trials and more study subjects with PCD will be needed to validate important observations from this work.
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107605
This page is being maintained by Thomas Krichel. It was last updated on 2023‒05‒28 at 14:58:18.