bims-medebr 2022-04-24 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒04‒24
28 papers selected by
Regina F. Fernández
Johns Hopkins University

Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer's disease mouse model.
Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver-Brain Axis for Lipid Homeostasis.
Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.
Neuroprotective effects of DHA-derived peroxidation product 4(RS)-4-F4t-neuroprostane on microglia.
Glucose metabolism and AD: evidence for a potential diabetes type 3.
The brain-from neurodevelopment to neurodegeneration.
From a Demand-Based to a Supply-Limited Framework of Brain Metabolism.
HMTM-Mediated Enhancement of Brain Bioenergetics in a Mouse Tauopathy Model Is Blocked by Chronic Administration of Rivastigmine.
Mitochondrial localization of calpain-13 in mouse brain.
Glucose Metabolism, Neural Cell Senescence and Alzheimer's Disease.
Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?
Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.
Sphingolipid Metabolism as a New Predictive Target Correlated with Aging and AD: A Transcriptomic Analysis.
Association between brain metabolism and clinical course of motor functional neurological disorders.
Steady-State Levels of Miro1 Linked to Phosphorylation at Serine 156 and Mitochondrial Respiration in Dopaminergic Neurons.
Cloning of a new form of EAAT2/GLT-1 from human and rodent brains.
VGLUT3 ablation differentially modulates glutamate receptor densities in mouse brain.
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease.
Mitochondrial Extracellular Vesicles in CNS Disorders: New Frontiers in Understanding the Neurological Disorders of the Brain.
The blood-brain barrier-a metabolic ecosystem.
A study of severe malnutrition in Malawian children illustrates the need for appropriate lipid nutrition to protect the brain.
Alteration in the Expression of Genes Involved in Cerebral Glucose Metabolism as a Process of Adaptation to Stressful Conditions.
The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy.
Mitochondrial and Neuronal Dysfunctions in L1 Mutant Mice.
Plasma Lipid Profiles Change with Increasing Numbers of Mild Traumatic Brain Injuries in Rats.
The Role of Major Facilitator Superfamily Domain-Containing 2a in the Central Nervous System.
Phosphatidylglycerol Supplementation Alters Mitochondrial Morphology and Cardiolipin Composition.
The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids.

Nat Commun. 2022 Apr 20. 13(1): 2061

Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer's disease mouse model.

Laura K Hamilton, Gaël Moquin-Beaudry, Chenicka L Mangahas, Federico Pratesi, Myriam Aubin, Anne Aumont, Sandra E Joppé, Alexandre Légiot, Annick Vachon, Mélanie Plourde, Catherine Mounier, Martine Tétreault, Karl J L Fernandes.

The defining features of Alzheimer's disease (AD) include alterations in protein aggregation, immunity, lipid metabolism, synapses, and learning and memory. Of these, lipid abnormalities are the least understood. Here, we investigate the role of Stearoyl-CoA desaturase (SCD), a crucial regulator of fatty acid desaturation, in AD pathogenesis. We show that inhibiting brain SCD activity for 1-month in the 3xTg mouse model of AD alters core AD-related transcriptomic pathways in the hippocampus, and that it concomitantly restores essential components of hippocampal function, including dendritic spines and structure, immediate-early gene expression, and learning and memory itself. Moreover, SCD inhibition dampens activation of microglia, key mediators of spine loss during AD and the main immune cells of the brain. These data reveal that brain fatty acid metabolism links AD genes to downstream immune, synaptic, and functional impairments, identifying SCD as a potential target for AD treatment.

DOI: https://doi.org/10.1038/s41467-022-29506-y
Metabolites. 2022 Apr 14. pii: 351. [Epub ahead of print]12(4):

Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver-Brain Axis for Lipid Homeostasis.

Sofia Milosavljevic, Kevin E Glinton, Xiqi Li, Cláudia Medeiros, Patrick Gillespie, John R Seavitt, Brett H Graham, Sarah H Elsea.

  Though biallelic variants in SLC13A5 are known to cause severe encephalopathy, the mechanism of this disease is poorly understood. SLC13A5 protein deficiency reduces citrate transport into the cell. Downstream abnormalities in fatty acid synthesis and energy generation have been described, though biochemical signs of these perturbations are inconsistent across SLC13A5 deficiency patients. To investigate SLC13A5-related disorders, we performed untargeted metabolic analyses on the liver, brain, and serum from a Slc13a5-deficient mouse model. Metabolomic data were analyzed using the connect-the-dots (CTD) methodology and were compared to plasma and CSF metabolomics from SLC13A5-deficient patients. Mice homozygous for the Slc13a5tm1b/tm1b null allele had perturbations in fatty acids, bile acids, and energy metabolites in all tissues examined. Further analyses demonstrated that for several of these molecules, the ratio of their relative tissue concentrations differed widely in the knockout mouse, suggesting that deficiency of Slc13a5 impacts the biosynthesis and flux of metabolites between tissues. Similar findings were observed in patient biofluids, indicating altered transport and/or flux of molecules involved in energy, fatty acid, nucleotide, and bile acid metabolism. Deficiency of SLC13A5 likely causes a broader state of metabolic dysregulation than previously recognized, particularly regarding lipid synthesis, storage, and metabolism, supporting SLC13A5 deficiency as a lipid disorder.

Keywords:  SLC13A5; SLC13A5 deficiency; bile acid metabolism; citrate transport; lipid synthesis; lipid utilization; liver-brain axis; untargeted metabolomics

DOI:  https://doi.org/10.3390/metabo12040351
Neuron. 2022 Apr 15. pii: S0896-6273(22)00251-3. [Epub ahead of print]

Programming axonal mitochondrial maintenance and bioenergetics in neurodegeneration and regeneration.

Xiu-Tang Cheng, Ning Huang, Zu-Hang Sheng.

  Mitochondria generate ATP essential for neuronal growth, function, and regeneration. Due to their polarized structures, neurons face exceptional challenges to deliver mitochondria to and maintain energy homeostasis throughout long axons and terminal branches where energy is in high demand. Chronic mitochondrial dysfunction accompanied by bioenergetic failure is a pathological hallmark of major neurodegenerative diseases. Brain injury triggers acute mitochondrial damage and a local energy crisis that accelerates neuron death. Thus, mitochondrial maintenance defects and axonal energy deficits emerge as central problems in neurodegenerative disorders and brain injury. Recent studies have started to uncover the intrinsic mechanisms that neurons adopt to maintain (or reprogram) axonal mitochondrial density and integrity, and their bioenergetic capacity, upon sensing energy stress. In this review, we discuss recent advances in how neurons maintain a healthy pool of axonal mitochondria, as well as potential therapeutic strategies that target bioenergetic restoration to power neuronal survival, function, and regeneration.

Keywords:  axonal transport; bioenergetic failure; brain injury; energy deficits; energy metabolism; energy recovery; ischemia; mitochondrial anchoring; mitochondrial quality control; neurodegeneration

DOI:  https://doi.org/10.1016/j.neuron.2022.03.015
Free Radic Biol Med. 2022 Apr 18. pii: S0891-5849(22)00148-4. [Epub ahead of print]

Neuroprotective effects of DHA-derived peroxidation product 4(RS)-4-F4t-neuroprostane on microglia.

Xue Geng, Jean-Marie Galano, Camille Oger, Grace Y Sun, Thierry Durand, James C Lee.

  The abundance of docosahexaenoic acid (DHA) in brain membrane phospholipids has stimulated studies to explore its role in neurological functions. Upon released from phospholipids, DHA undergoes enzymatic reactions resulting in synthesis of bioactive docosanoids and prostanoids. However, these phospholipids are also prone to non-enzymatic reactions leading to more complex pattern of metabolites. A non-enzymatic oxidized product of DHA, 4(RS)-4-F4t-Neuroprostane (44FNP), has been identified in cardiac and brain tissues. In this study, we examined effects of the 44FNP on oxidative and inflammatory responses in microglial cells treated with lipopolysaccharide (LPS). The 44FNP attenuated LPS-induced production of reactive oxygen species (ROS) in both primary and immortalized microglia (BV2). It also attenuated LPS-induced inflammation through suppressing NFκB-p65 and levels of iNOS and TNFα. In addition, 44FNP also suppressed LPS-induced mitochondrial dysfunction and upregulated the Nrf2/HO-1 antioxidative pathway. In sum, these findings with microglial cells demonstrated neuroprotective effects of this 44FNP and shed light into the potential of nutraceutical therapy for neurodegenerative diseases.

Keywords:  4(RS)-4-F4t-Neuroprostane; Antioxidant, and anti-inflammatory; Microglia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.04.002
Alzheimers Res Ther. 2022 Apr 20. 14(1): 56

Glucose metabolism and AD: evidence for a potential diabetes type 3.

Andrea González, Camila Calfío, Macarena Churruca, Ricardo B Maccioni.

  BACKGROUND: Alzheimer's disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.METHODS: We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer's pathogenesis.
CONCLUSIONS: In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.

Keywords:  Alzheimer’s disease; ER stress; Glucose metabolism impairment; Insulin resistance; Tau posttranslational modifications

DOI:  https://doi.org/10.1186/s13195-022-00996-8
FEBS J. 2022 Apr;289(8): 2010-2012

The brain-from neurodevelopment to neurodegeneration.

Andrey Y Abramov.

  The brain is the organ that orchestrates the whole body. To do so, neurons and glia in different brain regions have evolved to be highly specialized and are regulated by diverse receptors and neuro- and gliotransmitters. Some of the features of the brain, including a protective brain-blood barrier, high-energy demand, and electrical activity, mean that neurons and astrocytes are uniquely diverse components of tissue that vary greatly even across brain regions. This Special Issue features 19 review articles that cover different aspects of the broad field of neuroscience-from neurodevelopment, physiology and memory formation to the mechanisms underlying the development of neurodegenerative diseases.

Keywords:  astrocyte; brain; neurodegeneration; neurodevelopment; neuron

DOI:  https://doi.org/10.1111/febs.16436
Front Integr Neurosci. 2022 ;16 818685

From a Demand-Based to a Supply-Limited Framework of Brain Metabolism.

Suzana Herculano-Houzel, Douglas L Rothman.

  What defines the rate of energy use by the brain, as well as per neurons of different sizes in different structures and animals, is one fundamental aspect of neuroscience for which much has been theorized, but very little data are available. The prevalent theories and models consider that energy supply from the vascular system to different brain regions is adjusted both dynamically and in the course of development and evolution to meet the demands of neuronal activity. In this perspective, we offer an alternative view: that regional rates of energy use might be mostly constrained by supply, given the properties of the brain capillary network, the highly stable rate of oxygen delivery to the whole brain under physiological conditions, and homeostatic constraints. We present evidence that these constraints, based on capillary density and tissue oxygen homeostasis, are similar between brain regions and mammalian species, suggesting they derive from fundamental biophysical limitations. The same constraints also determine the relationship between regional rates of brain oxygen supply and usage over the full physiological range of brain activity, from deep sleep to intense sensory stimulation, during which the apparent uncoupling of blood flow and oxygen use is still a predicted consequence of supply limitation. By carefully separating "energy cost" into energy supply and energy use, and doing away with the problematic concept of energetic "demands," our new framework should help shine a new light on the neurovascular bases of metabolic support of brain function and brain functional imaging. We speculate that the trade-offs between functional systems and even the limitation to a single attentional spot at a time might be consequences of a strongly supply-limited brain economy. We propose that a deeper understanding of brain energy supply constraints will provide a new evolutionary understanding of constraints on brain function due to energetics; offer new diagnostic insight to disturbances of brain metabolism; lead to clear, testable predictions on the scaling of brain metabolic cost and the evolution of brains of different sizes; and open new lines of investigation into the microvascular bases of progressive cognitive loss in normal aging as well as metabolic diseases.

Keywords:  blood flow; brain metabolism; capillary density; fMRI; neurovascular uncoupling; oxygen extraction factor

DOI:  https://doi.org/10.3389/fnint.2022.818685
Biomedicines. 2022 Apr 07. pii: 867. [Epub ahead of print]10(4):

HMTM-Mediated Enhancement of Brain Bioenergetics in a Mouse Tauopathy Model Is Blocked by Chronic Administration of Rivastigmine.

Renato X Santos, Valeria Melis, Elizabeth A Goatman, Michael Leith, Thomas C Baddeley, John M D Storey, Gernot Riedel, Claude M Wischik, Charles R Harrington.

  The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer's disease (AD) clinical trials; the activity was reduced in patients receiving symptomatic therapies. The methylthionine (MT) moiety has been reported to increase the clearance of pathological tau and to enhance mitochondrial activity, which is impaired in AD patients. In line 1 (L1) mice (a model of AD), HMTM (5/15 mg/kg) was administered either as a monotherapy or as an add-on to a chronic administration with the cholinesterase inhibitor rivastigmine (0.1/0.5 mg/kg) to explore mitochondrial function and energy substrate utilization as potential targets of drug interference. Compared with wild-type NMRI mice, the L1 mice accumulated greater levels of l-lactate and of the LDH-A subunit responsible for the conversion of pyruvate into l-lactate. In contrast, the levels of LDH-B and mitochondrial ETC subunits and the activity of complexes I and IV was not altered in the L1 mice. The activity of complex I and complex IV tended to increase with the HMTM dosing, in turn decreasing l-lactate accumulation in the brains of the L1 mice, despite increasing the levels of LDH-A. The chronic pre-dosing of the L1 mice with rivastigmine partially prevented the enhancement of the activity of complexes I and IV by HMTM and the increase in the levels of LDH-A while further reducing the levels of l-lactate. Thus, HMTM in combination with rivastigmine leads to a depletion in the energy substrate l-lactate, despite bioenergetic production not being favoured. In this study, the changes in l-lactate appear to be regulated by LDH-A, since neither of the experimental conditions affected the levels of LDH-B. The data show that HMTM monotherapy facilitates the use of substrates for energy production, particularly l-lactate, which is provided by astrocytes, additionally demonstrating that a chronic pre-treatment with rivastigmine prevented most of the HMTM-associated effects.

Keywords:  Alzheimer’s disease; HMTM; bioenergetics; hydromethylthionine; lactate; mitochondria; rivastigmine; tau aggregation inhibitor; tauopathy

DOI:  https://doi.org/10.3390/biomedicines10040867
Biochem Biophys Res Commun. 2022 Apr 04. pii: S0006-291X(22)00515-0. [Epub ahead of print]609 149-155

Mitochondrial localization of calpain-13 in mouse brain.

Eiji Funajima, Ginga Ito, Eri Ishiyama, Kinji Ishida, Taku Ozaki.

  Calpains are Ca2+-dependent cysteine proteases involved in various intercellular physiological functions. Although most calpains exist in the cytosol, four isoforms of calpain (calpains-1, -2, -5, -10) are also localized in the mitochondria. In the present study, we examined the mitochondrial localization of calpain-13, as a novel mitochondrial calpain, in C57BL/6J mice. The tissue distribution and mitochondrial subfractionation of calpain-13 were investigated using western blotting. Calpain-13 was present in both the mitochondrial membrane (outer membrane and inner membrane) and soluble (intermembrane space and matrix) fractions. Through immunohistochemistry, calpain-13 was found to be expressed in the cerebral cortex and hippocampus of the mouse brain. We further confirmed the localization of calpain-13 in the mitochondria of the mouse brain using immunoelectron microscopy. Our present study thus revealed that calpain-13 is localized in the mitochondria, in addition to the cytosol, in the mouse brain. Future studies investigating the enzymatic properties and physiological functions of both cytosolic and mitochondrial calpain-13 will shed light on the potential involvement of calpain-13 in neurodegenerative diseases including Parkinson's disease and Alzheimer's disease.

Keywords:  Brain; Calpain-13; Cerebral cortex; Hippocampus; Mitochondria

DOI:  https://doi.org/10.1016/j.bbrc.2022.04.002
Int J Mol Sci. 2022 Apr 14. pii: 4351. [Epub ahead of print]23(8):

Glucose Metabolism, Neural Cell Senescence and Alzheimer's Disease.

Qianqian Wang, Linyan Duan, Xingfan Li, Yifu Wang, Wenna Guo, Fangxia Guan, Shanshan Ma.

  Alzheimer's disease (AD), an elderly neurodegenerative disorder with a high incidence and progressive memory decline, is one of the most expensive, lethal, and burdening diseases. To date, the pathogenesis of AD has not been fully illustrated. Emerging studies have revealed that cellular senescence and abnormal glucose metabolism in the brain are the early hallmarks of AD. Moreover, cellular senescence and glucose metabolism disturbance in the brain of AD patients may precede amyloid-β deposition or Tau protein phosphorylation. Thus, metabolic reprogramming targeting senescent microglia and astrocytes may be a novel strategy for AD intervention and treatment. Here, we recapitulate the relationships between neural cell senescence and abnormal glucose metabolism (e.g., insulin signaling, glucose and lactate metabolism) in AD. We then discuss the potential perspective of metabolic reprogramming towards an AD intervention, providing a theoretical basis for the further exploration of the pathogenesis of and therapeutic approach toward AD.

Keywords:  Alzheimer’s disease; glucose metabolism; metabolic reprogramming; neural cell senescence; therapeutics

DOI:  https://doi.org/10.3390/ijms23084351
Front Cell Dev Biol. 2022 ;10 874596

Mitochondrial Respiratory Chain Dysfunction-A Hallmark Pathology of Idiopathic Parkinson's Disease?

Irene H Flønes, Charalampos Tzoulis.

  Parkinson's disease (PD) is the most common age-dependent neurodegenerative synucleinopathy. Loss of dopaminergic neurons of the substantia nigra pars compacta, together with region- and cell-specific aggregations of α -synuclein are considered main pathological hallmarks of PD, but its etiopathogenesis remains largely unknown. Mitochondrial dysfunction, in particular quantitative and/or functional deficiencies of the mitochondrial respiratory chain (MRC), has been associated with the disease. However, after decades of research in this field, the pervasiveness and anatomical extent of MRC dysfunction in PD remain largely unknown. Moreover, it is not known whether the observed MRC defects are pathogenic, compensatory responses, or secondary epiphenomena. In this perspective, we give an overview of current evidence for MRC dysfunction in PD, highlight pertinent knowledge gaps, and propose potential strategies for future research.

Keywords:  Parkinson's disease; mitochondria; mitochondrial complex I; neurodegeneration; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fcell.2022.874596
Stem Cell Rev Rep. 2022 Apr 23.

Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.

Xingyu Gao, Xiao Yu, Chang Zhang, Yiming Wang, Yanan Sun, Hui Sun, Haiying Zhang, Yingai Shi, Xu He.

  Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.

Keywords:  Aging; Cellular senescence; Mitochondrial metabolism; Telomeres

DOI:  https://doi.org/10.1007/s12015-022-10370-8
Medicina (Kaunas). 2022 Mar 30. pii: 493. [Epub ahead of print]58(4):

Sphingolipid Metabolism as a New Predictive Target Correlated with Aging and AD: A Transcriptomic Analysis.

Simone D'Angiolini, Luigi Chiricosta, Emanuela Mazzon.

  Background and objectives: Alzheimer's disease (AD) is the most common form of dementia characterized by memory loss and executive dysfunction. To date, no markers can effectively predict the onset of AD and an early diagnosis is increasingly necessary. Age represents an important risk factor for the disease but it is not known whether it is the trigger event. Materials and Methods: We downloaded transcriptomic data related to post-mortem brain of thirty samples gathered as young without AD (Young), old without AD (Old), and old suffering from AD (OAD) groups. Results: Our results showed that steroid biosynthesis was enriched and associated with aging, while sphingolipid metabolism was related to both aging and AD. Specifically, sphingolipid metabolism is involved in the deregulation of CERS2, UGT8, and PLPP2. These genes are downregulated in Young and Old groups as compared with upregulated between Old and OAD groups. Moreover, the analysis of the interaction networks revealed that GABAergic synapse and Hippo signaling pathways were altered in AD condition along with mitochondrial metabolism and RNA processing. Conclusions: Observing the particular trend of genes related to sphingolipid metabolism that are downregulated during normal aging and start to be upregulated with the onset of AD, we suppose that sphingolipids could be early markers for the disease.

Keywords:  Alzheimer’s disease; aging; interactome; sphingolipid metabolism; transcriptome

DOI:  https://doi.org/10.3390/medicina58040493
Brain. 2022 Apr 21. pii: awac146. [Epub ahead of print]

Association between brain metabolism and clinical course of motor functional neurological disorders.

Ismael Conejero, Laurent Collombier, Jorge Lopez-Castroman, Thibault Mura, Sandrine Alonso, Emilie Olié, Vincent Boudousq, Fabrice Boulet, Caroline Arquizan, Charlotte Boulet, Anne Wacongne, Camille Heitz, Christel Castelli, Stéphane Mouchabac, Philippe Courtet, Mocrane Abbar, Eric Thouvenot.

  Features of resting brain metabolism in motor functional neurological disorder are poorly characterized. This study aimed to investigate the alterations of resting brain metabolism in a cohort of patients experiencing a first episode of motor functional neurological disorder with recent symptom onset, and their association with persistent disability after 3 months. Patients eligible for inclusion were diagnosed with first episode of motor functional neurological disorder, were free from bipolar disorder, substance use disorder, schizophrenia, psychogenic non-epileptic seizure or any chronic or acute organic neurological disorder. Exclusion criteria included current suicidal ideation, antipsychotic intake and previous history of functional neurological disorder. Nineteen patients were recruited in Psychiatry and Neurology departments from 2 hospitals. Resting brain metabolism measured with 18F-fluorodeoxyglucose positron emission computed tomography at baseline and 3 months was compared to 23 controls without neurological impairment. Disability was scored using Expanded Disability Status Scale and National Institutes of Health Stroke Scale score at baseline and 3 months. Correlations were calculated with Spearman correlation coefficient. Hypometabolism was found at baseline in bilateral frontal regions in patients versus controls, disappearing by 3 months. The patients with Expanded Disability Status Scale score improvement showed greater resting state activity of prefrontal dorsolateral cortex, right orbito-frontal cortex and bilateral frontopolar metabolism at 3 months versus other patients. The resting state metabolism of the right subgenual anterior cingular cortex at baseline was negatively correlated with improvement of motor disability (measured with Expanded Disability Status Scale) between inclusion and 3 months (r=-0.75, p = 0.0018) and with change in motor symptoms assessed with the National Institutes of Health Stroke Scale (r=-0.81, p= 0.0005). The resting state metabolism of the left subgenual anterior cingular cortex at baseline was negatively correlated with improvement in Expanded Disability Status Scale and National Institutes of Health Stroke Scale scores between inclusion and 3 months (r= -0.65, p = 0.01 and r= -0.75, p = 0.0021, respectively). The negative association between the brain metabolism of the right subgenual anterior cingular cortex at baseline and change in National Institutes of Health Stroke Scale score remained significant (r=-0.81, p= 0.0414) after correction for multiple comparisons. Our findings suggest the existence of metabolic "state markers" associated with motor disability and that brain markers are associated with motor recovery in functional neurological disorder patients.

Keywords:  brain metabolism; disability; functional neurological disorder; motor symptoms; outcome measures

DOI:  https://doi.org/10.1093/brain/awac146
Cells. 2022 Apr 08. pii: 1269. [Epub ahead of print]11(8):

Steady-State Levels of Miro1 Linked to Phosphorylation at Serine 156 and Mitochondrial Respiration in Dopaminergic Neurons.

Lisa Schwarz, Julia C Fitzgerald.

  Miro1 has emerged as an interesting target to study Parkinson's disease-relevant pathways since it is a target of PINK1 and Parkin. Miro1 is a mitochondrial GTPase with the primary function of facilitating mitochondrial movement, and its knockout in mice is postnatally lethal. Here, we investigated the effect of the artificial RHOT1/Miro1 S156A mutation since it is a putative PINK1 phosphorylation site shown to be involved in Miro1 degradation and mitochondrial arrest during mitophagy. We gene-edited a homozygous phospho-null Miro1 S156A mutation in induced pluripotent stem cells to study the mutation in human dopaminergic neurons. This mutation causes a significant depletion of Miro1 steady-state protein levels and impairs further Miro1 degradation upon CCCP-induced mitophagy. However, mitochondrial mass measured by Tom20 protein levels, as well as mitochondrial area, are not affected in Miro1 S156A neurons. The mitochondria are slightly lengthened, which is in line with their increased turnover. Under basal conditions, we found no discernable effect of the mutation on mitochondrial movement in neurites. Interestingly, the S156A mutation leads to a significant reduction of mitochondrial oxygen consumption, which is accompanied by a depletion of OXPHOS complexes III and V. These effects are not mirrored by Miro1 knockdown in neuroblastoma cells, but they are observed upon differentiation. Undifferentiated Miro1 S156A neural precursor cells do not have decreased Miro1 levels nor OXPHOS complexes, suggesting that the effect of the mutation is tied to development. In mature dopaminergic neurons, the inhibition of Miro1 Ser156 phosphorylation elicits a mild loss of mitochondrial quality involving reduced mitochondrial membrane potential, which is sufficient to induce compensatory events involving OXPHOS. We suggest that the mechanism governing Miro1 steady-state levels depends on differentiation state and metabolic demand, thus underscoring the importance of this pathway in the pathobiology of Parkinson's disease.

Keywords:  Miro1; PINK1; Parkinson’s disease; mitochondria

DOI:  https://doi.org/10.3390/cells11081269
Neurosci Lett. 2022 Apr 16. pii: S0304-3940(22)00194-X. [Epub ahead of print] 136637

Cloning of a new form of EAAT2/GLT-1 from human and rodent brains.

A Lee, S Klinkradt, P A McCombe, D V Pow.

  Glutamate transporter 1 is the principal transporter that mediates glutamate clearance in the mammalian brain. In rodents, it is referred to as GLT-1, whereas in humans it is referred to as EAAT2. We have cloned a novel and abundantly expressed carboxyl-terminal splice variant of this transporter in both rodents and humans, which we denote as GLT-1d/EAAT2d. The novel splice variant results from usage of internal splice sites and the splicing event leads to novel extra sequence spliced in after exon 10. The open reading frames of GLT-1d and EAAT2d encode proteins of 572 and 566 amino acids respectively; both contain a C-terminal PDZ motif. When expressed in COS7 cells, the proteins function as glutamate transporters that are inhibited by dihydrokainate (a GLT-1/EAAT2 transporter inhibitor). RT-PCR amplification using GLT-1d specific primers confirmed expression of message in all brain regions examined (forebrain, midbrain, hindbrain and cerebellum) as well as spinal cord, astrocyte cultures, retina and peripheral tissues (liver, testis, small intestine and lung). Quantitative RT-PCR analysis showed that expression of GLT-1d is developmentally regulated. In adult human brain, EAAT2d message is ∼30% of the level of EAAT2a message (the most abundant form), potentially making it the second most abundantly expressed form of EAAT2 in the brain. The amino terminal region of GLT-1d is also alternately spliced; the brain and testis forms contain a sequence corresponding to the amino acid sequence MASTEG whereas the corresponding liver sequence is MVS. In summary, we have cloned a novel EAAT2/GLT-1 splice variant from human and rodent brains. The splice variant is abundantly expressed in the brain, spinal cord, retina, liver and testis; it is a functional glutamate transporter; therefore, we conclude that it will likely have a functional role in glutamate homeostasis in the rodent and human nervous system, during development, adulthood, and plausibly in pathological states.

Keywords:  EAAT2; GLT-1; cloning; development brain; glutamate transporter; splice variant

DOI:  https://doi.org/10.1016/j.neulet.2022.136637
eNeuro. 2022 Apr 20. pii: ENEURO.0041-22.2022. [Epub ahead of print]

VGLUT3 ablation differentially modulates glutamate receptor densities in mouse brain.

Karim S Ibrahim, Salah El Mestikawy, Khaled S Abd-Elrahman, Stephen S G Ferguson.

  Type 3 vesicular glutamate transporter (VGLUT3) represents a unique modulator of glutamate release from both non-glutamatergic and glutamatergic varicosities within the brain. Despite its limited abundance, VGLUT3 is vital for regulation of glutamate signaling, and therefore modulates the activity of various brain microcircuits. However, little is known on how glutamate receptors are regulated by VGLUT3 across different brain regions. Here, we employed VGLUT3 constitutive knockout (VGLUT3-/-) mice and explored how VGLUT3 deletion influences total and cell surface expression of different ionotropic and metabotropic glutamate receptors. VGLUT3 deletion upregulated the overall expression of metabotropic glutamate receptors, mGluR5 and mGluR2/3 in the cerebral cortex. In contrast, no change in levels of ionotropic NMDARs glutamate receptors were observed in the cerebral cortex of VGLUT3-/- mice. We noted significant reduction in cell surface levels of mGluR5, NMDAR2A, NMDAR2B, as well as reductions in dopaminergic D1 (D1R) and muscarinic M1 receptors (M1 mAChR) in the hippocampus of VGLUT3-/- mice. Furthermore, mGluR2/3 total expression and mGluR5 cell surface levels were elevated in the striatum of VGLUT3-/- mice. Lastly, AMPAR subunit GluA1 was significantly upregulated throughout cortical, hippocampal, and striatal brain regions of VGLUT3-/- mice. Together, these findings complement and further support the evidence that VGLUT3 dynamically regulate glutamate receptors densities in several brain regions. These results suggest that VGLUT3 may play an intricate role in shaping glutamatergic signaling and plasticity in several brain areas.SIGNIFICANCE STATEMENTVGLUT3 is atypical vesicular glutamate transporter that is discretely expressed by subpopulations of non-glutamatergic neurons within the brain. Through these neurons, VGLUT3 regulates mood, movement coordination, rewarding behavior, and cognition. Despite extensive research on VGLUT3 neurotransmission in non-glutamatergic neurons, little is known on how glutamate receptors are regulated by VGLUT3 signaling in the brain. Using VGLUT3 knockout in mice, we show that VGLUT3 differentially regulates glutamate receptor densities in various brain regions, further supporting its critical role in regulating synaptic function and plasticity in brain circuits.

Keywords:  GPCR; Glutamate; brain; synaptic plasticity; transporter

DOI:  https://doi.org/10.1523/ENEURO.0041-22.2022
Neurobiol Aging. 2022 Mar 22. pii: S0197-4580(22)00055-0. [Epub ahead of print]115 20-28

ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease.

Yonghe Li, Jesse R Macyczko, Chia-Chen Liu, Guojun Bu.

  APOE4 is the first identified genetic risk factor and remains as the strongest predictor for late-onset Alzheimer's disease (AD). Studies of AD patients, AD patient-specific induced pluripotent stem cell-derived neurons and cerebral organoids, and human apoE4-expressing and apoE-deficient mouse models clearly demonstrate that apoE4 provokes neuroinflammation, impairs cerebrovasculature, and exacerbates amyloid and tau pathologies. ApoE expression is greatly up-regulated in disease-associated microglia in mouse models of amyloidosis and in human microglia from AD brains. Importantly, genetic knock-down or depletion of apoE in mice greatly attenuates neuroinflammation and alleviates amyloid and tau pathologies. Similar beneficial effects can be achieved when apoE reduction is induced by the overexpression of apoE metabolic receptor LDLR. Toward therapeutic implications, administration of apoE antisense oligonucleotides or apoE siRNAs leads to significant pharmacologic effects, i.e., significant alleviation of AD pathologies in mouse models. Therefore, apoE reduction represents a promising therapeutic strategy for the treatment of AD patients carrying the APOE ε4 allele. In this review, we summarize evidence and rationale on why and how we target apoE4 reduction for AD therapy.

Keywords:  Alzheimer's disease; ApoE4; LDLR; Therapeutic approach

DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.03.011
Front Mol Biosci. 2022 ;9 840364

Mitochondrial Extracellular Vesicles in CNS Disorders: New Frontiers in Understanding the Neurological Disorders of the Brain.

Mary F Nakamya, Susmita Sil, Shilpa Buch, Ramin M Hakami.

  Recent findings have highlighted potential diagnostic and prognostic values of extracellular vesicles (EVs) that contain mitochondrial derived components for neurological disorders. Furthermore, functional influences of vesicles carrying mitochondrial components have been reported. In particular, this includes indications of crosstalk with mitophagy to influence progression of various CNS disorders. In this mini-review, we discuss the current state of knowledge about this intriguing class of vesicles in neurological disorders of the CNS, and outline the lacunae and thus scope of further development in this fascinating field of study.

Keywords:  CNS disorders; extracellular vesicles; mitochondria; mitochondria-derived vesicles; mitochondrial dysfunction; mitophagy; oxidative stress

DOI:  https://doi.org/10.3389/fmolb.2022.840364
EMBO J. 2022 Apr 19. e111189

The blood-brain barrier-a metabolic ecosystem.

Marco Castro, Michael Potente.

A functional blood-brain barrier relies on a tightly controlled interplay between endothelial cells, pericytes, and astrocytes, which together form the neurovascular unit. Recent work by Lee et al (2022) discovers endothelial cell-derived lactate as a crucial metabolic fuel for brain pericytes, revealing a new way of CNS vascular communication that links nutrient metabolism to blood-brain barrier function.

DOI: https://doi.org/10.15252/embj.2022111189
Am J Clin Nutr. 2022 Apr 21. pii: nqab425. [Epub ahead of print]

A study of severe malnutrition in Malawian children illustrates the need for appropriate lipid nutrition to protect the brain.

Michael Crawford.

DOI: https://doi.org/10.1093/ajcn/nqab425
Brain Sci. 2022 Apr 13. pii: 498. [Epub ahead of print]12(4):

Alteration in the Expression of Genes Involved in Cerebral Glucose Metabolism as a Process of Adaptation to Stressful Conditions.

Mariola Herbet, Iwona Piątkowska-Chmiel, Monika Motylska, Monika Gawrońska-Grzywacz, Barbara Nieradko-Iwanicka, Jarosław Dudka.

  Exposure to chronic stress leads to disturbances in glucose metabolism in the brain, and changes in the functioning of neurons coexisting with the development of depression. The detailed molecular mechanism and cerebral gluconeogenesis during depression are not conclusively established. The aim of the research was to assess the expression of selected genes involved in cerebral glucose metabolism of mice in the validated animal paradigm of chronic stress. To confirm the induction of depression-like disorders, we performed three behavioral tests: sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST). In order to study the cerebral glucose metabolism of the brain, mRNA levels of the following genes were determined in the prefrontal cortex of mice: Slc2a3, Gapdh, Ldha, Ldhb, and Pkfb3. It has been shown that exogenous, chronic administration of corticosterone developed a model of depression in behavioral tests. There were statistically significant changes in the mRNA level of the Slc2a3, Ldha, Gapdh, and Ldhb genes. The obtained results suggest changes in cerebral glucose metabolism as a process of adaptation to stressful conditions, and may provide the basis for introducing new therapeutic strategies for chronic stress-related depression.

Keywords:  cerebral glucose metabolism; chronic stress; depression; gene expression

DOI:  https://doi.org/10.3390/brainsci12040498
Biomedicines. 2022 Apr 07. pii: 863. [Epub ahead of print]10(4):

The PINK1 Activator Niclosamide Mitigates Mitochondrial Dysfunction and Thermal Hypersensitivity in a Paclitaxel-Induced Drosophila Model of Peripheral Neuropathy.

Hye-Ji Jang, Young-Yeon Kim, Kang-Min Lee, Jung-Eun Shin, Jeanho Yun.

  Paclitaxel is a widely used anticancer drug that induces dose-limiting peripheral neuropathy. Mitochondrial dysfunction has been implicated in paclitaxel-induced neuronal damage and in the onset of peripheral neuropathy. We have previously shown that the expression of PINK1, a key mediator of mitochondrial quality control, ameliorated the paclitaxel-induced thermal hyperalgesia phenotype and restored mitochondrial homeostasis in Drosophila larvae. In this study, we show that the small-molecule PINK1 activator niclosamide exhibits therapeutic potential for paclitaxel-induced peripheral neuropathy. Specifically, niclosamide cotreatment significantly ameliorated the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae in a PINK1-dependent manner. Paclitaxel-induced alteration of the dendrite structure of class IV dendritic arborization (C4da) neurons was not reduced upon niclosamide treatment. In contrast, paclitaxel treatment-induced increases in both mitochondrial ROS and aberrant mitophagy levels in C4da neurons were significantly suppressed by niclosamide. In addition, niclosamide suppressed paclitaxel-induced mitochondrial dysfunction in human SH-SY5Y cells in a PINK1-dependent manner. These results suggest that niclosamide alleviates thermal hyperalgesia by attenuating paclitaxel-induced mitochondrial dysfunction. Taken together, our results suggest that niclosamide is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy with low toxicity in neurons and that targeting mitochondrial dysfunction is a promising strategy for the treatment of chemotherapy-induced peripheral neuropathy.

Keywords:  PINK1; mitochondrial dysfunction; niclosamide; paclitaxel; peripheral neuropathy

DOI:  https://doi.org/10.3390/biomedicines10040863
Int J Mol Sci. 2022 Apr 14. pii: 4337. [Epub ahead of print]23(8):

Mitochondrial and Neuronal Dysfunctions in L1 Mutant Mice.

Ludovica Congiu, Viviana Granato, Gabriele Loers, Ralf Kleene, Melitta Schachner.

  Adhesion molecules regulate cell proliferation, migration, survival, neuritogenesis, synapse formation and synaptic plasticity during the nervous system's development and in the adult. Among such molecules, the neural cell adhesion molecule L1 contributes to these functions during development, and in synapse formation, synaptic plasticity and regeneration after trauma. Proteolytic cleavage of L1 by different proteases is essential for these functions. A proteolytic fragment of 70 kDa (abbreviated L1-70) comprising part of the extracellular domain and the transmembrane and intracellular domains was shown to interact with mitochondrial proteins and is suggested to be involved in mitochondrial functions. To further determine the role of L1-70 in mitochondria, we generated two lines of gene-edited mice expressing full-length L1, but no or only low levels of L1-70. We showed that in the absence of L1-70, mitochondria in cultured cerebellar neurons move more retrogradely and exhibit reduced mitochondrial membrane potential, impaired Complex I activity and lower ATP levels compared to wild-type littermates. Neither neuronal migration, neuronal survival nor neuritogenesis in these mutants were stimulated with a function-triggering L1 antibody or with small agonistic L1 mimetics. These results suggest that L1-70 is important for mitochondrial homeostasis and that its absence contributes to the L1 syndrome phenotypes.

Keywords:  ATP; Complex I activity; L1CAM; cell adhesion molecule L1; mitochondria; neurite outgrowth; neuronal survival

DOI:  https://doi.org/10.3390/ijms23084337
Metabolites. 2022 Apr 02. pii: 322. [Epub ahead of print]12(4):

Plasma Lipid Profiles Change with Increasing Numbers of Mild Traumatic Brain Injuries in Rats.

Chidozie C Anyaegbu, Harrison Szemray, Sarah C Hellewell, Nathan G Lawler, Kerry Leggett, Carole Bartlett, Brittney Lins, Terence McGonigle, Melissa Papini, Ryan S Anderton, Luke Whiley, Melinda Fitzgerald.

  Mild traumatic brain injury (mTBI) causes structural, cellular and biochemical alterations which are difficult to detect in the brain and may persist chronically following single or repeated injury. Lipids are abundant in the brain and readily cross the blood-brain barrier, suggesting that lipidomic analysis of blood samples may provide valuable insight into the neuropathological state. This study used liquid chromatography-mass spectrometry (LC-MS) to examine plasma lipid concentrations at 11 days following sham (no injury), one (1×) or two (2×) mTBI in rats. Eighteen lipid species were identified that distinguished between sham, 1× and 2× mTBI. Three distinct patterns were found: (1) lipids that were altered significantly in concentration after either 1× or 2× F mTBI: cholesterol ester CE (14:0) (increased), phosphoserine PS (14:0/18:2) and hexosylceramide HCER (d18:0/26:0) (decreased), phosphoinositol PI(16:0/18:2) (increased with 1×, decreased with 2× mTBI); (2) lipids that were altered in response to 1× mTBI only: free fatty acid FFA (18:3 and 20:3) (increased); (3) lipids that were altered in response to 2× mTBI only: HCER (22:0), phosphoethanolamine PE (P-18:1/20:4 and P-18:0/20:1) (increased), lysophosphatidylethanolamine LPE (20:1), phosphocholine PC (20:0/22:4), PI (18:1/18:2 and 20:0/18:2) (decreased). These findings suggest that increasing numbers of mTBI induce a range of changes dependent upon the lipid species, which likely reflect a balance of damage and reparative responses.

Keywords:  lipid; lipidomics; liquid chromatography–mass spectrometry; mild traumatic brain injury; repeated mild traumatic brain injury

DOI:  https://doi.org/10.3390/metabo12040322
Cell Mol Neurobiol. 2022 Apr 19.

The Role of Major Facilitator Superfamily Domain-Containing 2a in the Central Nervous System.

Zhidong He, Yanan Zhao, Jing Sun.

  Major facilitator superfamily-domain containing 2a (Mfsd2a) is selectively expressed in vascular endotheliocytes and plays a crucial role in maintaining the integrity of the blood‒brain barrier and the transport of docosahexaenoic acid. It is currently recognized as the only molecule that inhibits endocytosis mediated by caveolae in brain endothelial cells. Mfsd2a gene knockout leads to an increase in the permeability of the blood-brain barrier from embryonic stages to adulthood while maintaining the normal pattern of the vascular network. In Mfsd2a knockout mice, the docosahexaenoic acid content is significantly reduced and associated with neuron loss, resulting in microcephaly and cognitive impairment. Based on the role of Mfsd2a in the central nervous system, it has been preliminarily suggested as a potential therapeutic target for drug delivery to the central nervous system. This paper reviews the current progress in Mfsd2a research and summarizes the physiological functions of Mfsd2a in the central nervous system and its role in the occurrence and development of a variety of neurological diseases.

Keywords:  Blood brain barrier; Central nervous system disease; DHA; Drug delivery; Mfsd2a

DOI:  https://doi.org/10.1007/s10571-022-01222-7
Membranes (Basel). 2022 Mar 31. pii: 383. [Epub ahead of print]12(4):

Phosphatidylglycerol Supplementation Alters Mitochondrial Morphology and Cardiolipin Composition.

I Chu, Ying-Chih Chen, Ruo-Yun Lai, Jui-Fen Chan, Ya-Hui Lee, Maria Balazova, Yuan-Hao Howard Hsu.

  The pathogenic variant of the TAZ gene is directly associated with Barth syndrome. Because tafazzin in the mitochondria is responsible for cardiolipin (CL) remodeling, all molecules related to the metabolism of CL can affect or be affected by TAZ mutation. In this study, we intend to recover the distortion of the mitochondrial lipid composition, especially CL, for Barth syndrome treatment. The genetically edited TAZ knockout HAP1 cells were demonstrated to be a suitable cellular model, where CL desaturation occurred and monolyso-CL (MLCL) was accumulated. From the species analysis by mass spectrometry, phosphatidylethanolamine showed changed species content after TAZ knockout. TAZ knockout also caused genetic down-regulation of PGS gene and up-regulation of PNPLA8 gene, which may decrease the biosynthesis of CLs and increase the hydrolysis product MLCL. Supplemented phosphatidylglycerol(18:1)2 (PG(18:1)2) was successfully biosynthesized to mature symmetrical CL and drastically decrease the concentration of MLCL to recover the morphology of mitochondria and the cristae shape of inner mitochondria. Newly synthesized mature CL may induce the down-regulation of PLA2G6 and PNPLA8 genes to potentially decrease MLCL production. The excess supplemented PG was further metabolized into phosphatidylcholine and phosphatidylethanolamine.

Keywords:  cardiolipin; mass spectrometry; phosphatidylglycerol; tafazzin

DOI:  https://doi.org/10.3390/membranes12040383
Microbiome. 2022 Apr 17. 10(1): 62

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids.

Weiping Xiao, Jiabin Su, Xinjie Gao, Heng Yang, Ruiyuan Weng, Wei Ni, Yuxiang Gu.

  BACKGROUND: Chronic cerebral hypoperfusion (CCH) underlies secondary brain injury following certain metabolic disorders and central nervous system (CNS) diseases. Dysregulation of the microbiota-gut-brain axis can exacerbate various CNS disorders through aberrantly expressed metabolites such as short-chain fatty acids (SCFAs). Yet, its relationship with CCH remains to be demonstrated. And if so, it is of interest to explore whether restoring gut microbiota to maintain SCFA metabolism could protect against CCH.RESULTS: Rats subjected to bilateral common carotid artery occlusion (BCCAO) as a model of CCH exhibited cognitive impairment, depressive-like behaviors, decreased gut motility, and compromised gut barrier functions. The 16S ribosomal RNA gene sequencing revealed an abnormal gut microbiota profile and decreased relative abundance of some representative SCFA producers, with the decreased hippocampal SCFAs as the further evidence. Using fecal microbiota transplantation (FMT), rats recolonized with a balanced gut microbiome acquired a higher level of hippocampal SCFAs, as well as decreased neuroinflammation when exposed to lipopolysaccharide. Healthy FMT promoted gut motility and gut barrier functions, and improved cognitive decline and depressive-like behaviors by inhibiting hippocampal neuronal apoptosis in BCCAO rats. Long-term SCFA supplementation further confirmed its neuroprotective effect in terms of relieving inflammatory response and hippocampal neuronal apoptosis following BCCAO.
CONCLUSION: Our results demonstrate that modulating the gut microbiome via FMT can ameliorate BCCAO-induced gut dysbiosis, cognitive decline, and depressive-like behaviors, possibly by enhancing the relative abundance of SCFA-producing floras and subsequently increasing SCFA levels. Video abstract.

Keywords:  Chronic cerebral hypoperfusion; Fecal microbiota transplantation; Gut dysbiosis; Gut microbiota; Short-chain fatty acids

DOI:  https://doi.org/10.1186/s40168-022-01255-6