bims-medebr 2024-04-07 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–04–07
29 papers selected by
Regina F. Fernández, Johns Hopkins University

What Is the Role of Lactate in Brain Metabolism, Plasticity, and Neurodegeneration?
Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.
Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer's disease mouse model.
Neuroprotective role of lactate in a human in vitro model of the ischemic penumbra.
Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study.
Linking mitochondria metabolism, developmental timing, and human brain evolution.
A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
Enhancing 7-dehydrocholesterol suppresses brain ferroptosis and tissue injury after neonatal hypoxia-ischemia.
Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients.
Tracing the lipidome in inborn errors of metabolism.
A novel mitochondrial DNA variant in MT-ND6: m.14430A>C p.(Trp82Gly) identified in a patient with Leigh syndrome and complex I deficiency.
A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.
Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.
Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).
PLD3 and PLD4 synthesize S,S -BMP, a key phospholipid enabling lipid degradation in lysosomes.
Mitochondrial dysfunction in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome: prospect use of antioxidants and mitochondrial nutrients.
Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.
TSG-6 mediated extracellular matrix modifications regulate hypoxic-ischemic brain injury.
Sex-specific changes in protein expression of membrane transporters in the brain cortex of 5xFAD mouse model of Alzheimer's disease.
Inhibition of DAPK3 suppresses radiation-induced cellular senescence by activation of a PGC1α-dependent metabolism pathway in brain endothelial cells.
Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.
Sex-specific antioxidant biomarker depletion in patients with a history of mild traumatic brain injury.
Targeting mitochondrial oxidative stress to protect against preterm birth and fetal brain injury via Nrf2 induction.
Metabolomics analysis revealed the neuroprotective role of 2-phosphoglyceric acid in hypoxic-ischemic brain damage through GPX4/ACSL4 axis regulation.
Imbalance in glucose metabolism regulates the transition of microglia from homeostasis to Disease Associated Microglia stage 1.
Pharmacological blockade of 2-AG degradation ameliorates clinical, neuroinflammatory and synaptic alterations in experimental autoimmune encephalomyelitis.
Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.
Brain functional and structural changes in diabetic children. How can intellectual development be optimized in type 1 diabetes?

Neurology. 2024 May 14. 102(9): e209378

What Is the Role of Lactate in Brain Metabolism, Plasticity, and Neurodegeneration?

Eduardo Benarroch.

DOI: https://doi.org/10.1212/WNL.0000000000209378
bioRxiv. 2024 Mar 20. pii: 2024.03.20.586011. [Epub ahead of print]

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Hao Zhang, Xianfeng Niu, Marissa A Laramie, Marion I Stunault, Jasmin Sponagel, Gary Patti, Leah Shriver, Vitaly Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals.
HIGHLIGHTS: Serum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle.The mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism.Acetylation of the MPC complex modulates mitochondrial pyruvate uptake.MPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals.

DOI: https://doi.org/10.1101/2024.03.20.586011
J Alzheimers Dis. 2024 Mar 30.

Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.

Marta Moreno-Rodriguez, Sylvia E Perez, Jonatan Martinez-Gardeazabal, Ivan Manuel, Michael Malek-Ahmadi, Rafael Rodriguez-Puertas, Elliott J Mufson.

   Background: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation.
Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD.
Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI).
Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI.
Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.

Keywords:  Alzheimer’s disease; MALDI-MSI; autoradiography; cholinergic; lipidomic; mild cognitive impairment; muscarinic receptor

DOI:  https://doi.org/10.3233/JAD-231485
Sci Rep. 2024 04 02. 14(1): 7742

Central inhibition of stearoyl-CoA desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer's disease mouse model.

Laura K Hamilton, Paule E H M'Bra, Sophia Mailloux, Manon Galoppin, Anne Aumont, Karl J L Fernandes.

Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer's disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD.

DOI: https://doi.org/10.1038/s41598-024-58272-8
Sci Rep. 2024 Apr 04. 14(1): 7973

Neuroprotective role of lactate in a human in vitro model of the ischemic penumbra.

Marta Cerina, Marloes Levers, Jason M Keller, Monica Frega.

In patients suffering from cerebral ischemic stroke, there is an urgent need for treatments to protect stressed yet viable brain cells. Recently, treatment strategies that induce neuronal activity have been shown to be neuroprotective. Here, we hypothesized that neuronal activation might maintain or trigger the astrocyte-to-neuron lactate shuttle (ANLS), whereby lactate is released from astrocytes to support the energy requirements of ATP-starved hypoxic neurons, and this leads to the observed neuroprotection. We tested this by using a human cell based in vitro model of the ischemic penumbra and investigating whether lactate might be neuroprotective in this setting. We found that lactate transporters are involved in the neuroprotective effect mediated by neuronal activation. Furthermore, we showed that lactate exogenously administered before hypoxia correlated with neuroprotection in our cellular model. In addition, stimulation of astrocyte with consequent endogenous production of lactate resulted in neuroprotection. To conclude, here we presented evidence that lactate transport into neurons contributes to neuroprotection during hypoxia providing a potential basis for therapeutic approaches in ischemic stroke.

DOI: https://doi.org/10.1038/s41598-024-58669-5
Front Neurosci. 2024 ;18 1344076

Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study.

Jessie Mosso, Guillaume Briand, Katarzyna Pierzchala, Dunja Simicic, Alejandra Sierra, Ali Abdollahzadeh, Ileana O Jelescu, Cristina Cudalbu.

   Introduction: Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites.
Methods: The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/μm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy).
Results: The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema.
Discussion: dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.

Keywords:  bile duct ligation; brain metabolism; diffusion-weighted magnetic resonance spectroscopy; hepatic encephalopathy; in vivo magnetic resonance spectroscopy; rat brain; ultra high magnetic field

DOI:  https://doi.org/10.3389/fnins.2024.1344076
Curr Opin Genet Dev. 2024 Mar 30. pii: S0959-437X(24)00031-5. [Epub ahead of print]86 102182

Linking mitochondria metabolism, developmental timing, and human brain evolution.

Pierre Casimir, Ryohei Iwata, Pierre Vanderhaeghen.

Changes in developmental timing are an important factor of evolution in organ shape and function. This is particularly striking for human brain development, which, compared with other mammals, is considerably prolonged at the level of the cerebral cortex, resulting in brain neoteny. Here, we review recent findings that indicate that mitochondria and metabolism contribute to species differences in the tempo of cortical neuron development. Mitochondria display species-specific developmental timeline and metabolic activity patterns that are highly correlated with the speed of neuron maturation. Enhancing mitochondrial activity in human cortical neurons results in their accelerated maturation, while its reduction leads to decreased maturation rates in mouse neurons. Together with other global and gene-specific mechanisms, mitochondria thus act as a cellular hourglass of neuronal developmental tempo and may thereby contribute to species-specific features of human brain ontogeny.

DOI: https://doi.org/10.1016/j.gde.2024.102182
Res Sq. 2024 Mar 22. pii: rs.3.rs-4047706. [Epub ahead of print]

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.

Martin Picard, Eugene Mosharov, Ayelet Rosenberg, Anna Monzel, Corey Osto, Linsey Stiles, Gorazd Rosoklija, Andrew Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline Mariani, Mihran Bakalian, David Sulzer, Philip De Jager, Vilas Menon, Orian Shirihai, John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten.

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3x3x3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.

DOI: https://doi.org/10.21203/rs.3.rs-4047706/v1
Sci Rep. 2024 Apr 04. 14(1): 7924

Enhancing 7-dehydrocholesterol suppresses brain ferroptosis and tissue injury after neonatal hypoxia-ischemia.

Thiago C Genaro-Mattos, Zeljka Korade, Namood-E Sahar, Jose Pedro Friedmann Angeli, Károly Mirnics, Eric S Peeples.

Neonatal hypoxic-ischemic brain injury (HIBI) results in part from excess reactive oxygen species and iron-dependent lipid peroxidation (i.e. ferroptosis). The vitamin D precursor 7-dehydrocholesterol (7-DHC) may inhibit iron-dependent lipid peroxidation. Primary neurons underwent oxygen and glucose deprivation (OGD) injury and treatment with 7-DHC-elevating medications such as cariprazine (CAR) or vehicle. Postnatal day 9 mice underwent sham surgery or carotid artery ligation and hypoxia and received intraperitoneal CAR. In neurons, CAR administration resulted in significantly increased cell survival compared to vehicle controls, whether administered 48 h prior to or 30 min after OGD, and was associated with increased 7-DHC. In the mouse model, malondialdehyde and infarct area significantly increased after HIBI in the vehicle group, which were attenuated by post-treatment with CAR and were negatively correlated with tissue 7-DHC concentrations. Elevating 7-DHC concentrations with CAR was associated with improved cellular and tissue viability after hypoxic-ischemic injury, suggesting a novel therapeutic avenue.

DOI: https://doi.org/10.1038/s41598-024-58579-6
J Pediatr Genet. 2024 Mar;13(1): 22-28

Inborn Errors of Ketogenesis: Novel Variants, Clinical Presentation, and Follow-Up in a Series of Four Patients.

Haseena Sait, Somya Srivastava, Somesh Kumar, Bijo Varughese, Manmohan Pandey, Manjunath Venkatramaiah, Parul Chaudhary, Amita Moirangthem, Kausik Mandal, Seema Kapoor.

  Inborn errors of ketogenesis are rare disorders that result in acute and fulminant decompensation during lipolytic stress, particularly in infants and children. These include mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS) deficiency and HMG-CoA lyase (HMGCL) deficiency. In this series, we describe the clinical, biochemical, and molecular profiles of four patients along with dietary interventions and their outcomes on a long-term follow-up. Two patients each of HMGCS and HMGCL deficiency were evaluated with clinical history, biochemical investigations, including tandem mass spectrometry (TMS) and urine gas chromatography-mass spectrometry (GCMS). Molecular analysis was performed by whole-exome sequencing, as well as exon array validated by long-range polymerase chain reaction. All individuals were diagnosed with acute metabolic decompensation in the early infancy period except one with HMGCL deficiency who had the first presentation at 5 years of age. Central nervous system manifestations, severe metabolic acidosis, hyperammonemia, hypoglycemia with a normal lactate, and absence of urinary ketones were observed in all the affected individuals. The disorder was life-threatening in three individuals and one succumbed to the illness. TMS was nonspecific and urine GCMS revealed dicarboxylic aciduria in HMGCS deficiency. Both the patients with HMGCL deficiency demonstrated elevated 3 hydroxyisovaleryl carnitine levels in TMS and metabolites of leucine degradation in urine GCMS. We identified five novel variants that included a large deletion involving exon 2 in HMGCL gene. There was no evidence of long-term neurological sequelae in the living individuals. Diet with moderation of fat intake was followed in two individuals with HMGCS deficiency. Low leucine and protein diet with moderation of fat intake was followed in the individual with HMGCL deficiency. All affected individuals are thriving well with no further major metabolic decompensation.

Keywords:  HMG-CoA lyase; HMG-CoA synthase; exon array; gas chromatography-mass spectrometry; hypoketotic hypoglycemia; ketogenesis; tandem mass spectrometry

DOI:  https://doi.org/10.1055/s-0042-1749362
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Mar 31. pii: S1388-1981(24)00041-6. [Epub ahead of print] 159491

Tracing the lipidome in inborn errors of metabolism.

Martina Zandl-Lang.

  Inborn errors of metabolism (IEM) represent a heterogeneous group of more than 1800 rare disorders, many of which are causing significant childhood morbidity and mortality. More than 100 IEM are linked to dyslipidaemia, but yet our knowledge in connecting genetic information with lipidomic data is limited. Stable isotope tracing studies of the lipid metabolism (STL) provide insights on the dynamic of cellular lipid processes and could thereby facilitate the delineation of underlying metabolic (patho)mechanisms. This mini-review focuses on principles as well as technical limitations of STL and describes potential clinical applications by discussing recently published STL focusing on IEM.

Keywords:  Flux studies; Lipids; Mass spectrometry; Metabolism; Rare diseases

DOI:  https://doi.org/10.1016/j.bbalip.2024.159491
Mol Genet Metab Rep. 2024 Jun;39 101078

A novel mitochondrial DNA variant in MT-ND6: m.14430A>C p.(Trp82Gly) identified in a patient with Leigh syndrome and complex I deficiency.

Surita Meldau, Sally Ackermann, Gillian Riordan, George F van der Watt, Careni Spencer, Sharika Raga, Kashief Khan, Dee M Blackhurst, Francois H van der Westhuizen.

  Leigh syndrome is a severe progressive mitochondrial disorder mainly affecting children under the age of 5 years. It is caused by pathogenic variants in any one of more than 75 known genes in the nuclear or mitochondrial genomes. A 19-week-old male infant presented with lactic acidosis and encephalopathy following a 2-week history of irritability, neuroregression and poor weight gain. He was hypotonic with pathological reflexes, impaired vision, and nystagmus. Brain MRI showed extensive bilateral symmetrical T2 hyperintense lesions in basal ganglia, thalami, and brainstem. Metabolic workup showed elevated serum alanine, and heavy lactic aciduria with increased ketones, fumarate, malate, and alpha-ketoglutarate as well as reduced succinate on urine organic acid analysis. Lactic acidemia persisted, with only a marginally elevated lactate:pyruvate ratio (16.46, ref. 0-10). He demised at age 7 months due to respiratory failure. Exome sequencing followed by virtual gene panel analysis for pyruvate metabolism and mitochondrial defects could not identify any nuclear cause for Leigh syndrome. Mitochondrial DNA (mtDNA) genome sequencing revealed 88% heteroplasmy for a novel variant, NC_012920.1(MT-ND6):m.14430A>C p.(Trp82Gly), in blood DNA. This variant was absent from the unaffected mother's blood, fibroblast, and urine DNA, and detected at a level of 5% in her muscle DNA. Mitochondrial respiratory chain analysis revealed markedly reduced mitochondrial complex I activity in patient fibroblasts (34% of parent and control cells), and reduced NADH-linked respirometry (less than half of parental and control cells), while complex II driven respirometry remained intact. The combined clinical, genetic, and biochemical findings suggest that the novel MT-ND6 variant is the likely cause of Leigh syndrome in this patient. The mitochondrial ND6 protein is a subunit of complex I. An interesting finding was the absence of a significantly elevated lactate:pyruvate ratio in the presence of severe lactatemia, which directed initial diagnostic efforts towards excluding a pyruvate metabolism defect. This case highlights the value of a multidisciplinary approach and complete genetic workup to diagnosing mitochondrial disorders in South African patients.

Keywords:  Complex I deficiency; Leigh syndrome; MT-DN6; Novel mtDNA variant

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101078
BMC Neurol. 2024 Apr 01. 24(1): 106

A randomized feasibility trial of medium chain triglyceride-supplemented ketogenic diet in people with Parkinson's disease.

Alexander H Choi, Melanie Delgado, Kong Y Chen, Stephanie T Chung, Amber Courville, Sara A Turner, Shanna Yang, Kayla Airaghi, Irene Dustin, Patrick McGurrin, Tianxia Wu, Mark Hallett, Debra J Ehrlich.

   BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD).
OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG).
METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity.
RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups.
CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease.
TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.

Keywords:  Biomarker; Clinical trial; Ketogenic diet; Ketosis; Parkinson’s disease; Pilot study

DOI:  https://doi.org/10.1186/s12883-024-03603-5
Sci Adv. 2024 Apr 05. 10(14): eadl2764

Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Jianfei Yan, Junjie Wu, Mingyue Xu, Min Wang, Weixiang Guo.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

DOI: https://doi.org/10.1126/sciadv.adl2764
Int J Mol Med. 2024 May;pii: 47. [Epub ahead of print]53(5):

Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review).

Pei Qin, Ye Sun, Liya Li.

  Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators of neuroinflammation. In addition to providing energy to cells, mitochondria also participate in the immunoinflammatory response of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis and epilepsy, by regulating processes such as cell death and inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, mitochondrial dynamics and calcium homeostasis imbalance may serve as underlying regulatory mechanisms for these diseases. Therefore, investigating mechanisms related to mitochondrial dysfunction may result in therapeutic strategies against chronic neuroinflammation and neurodegeneration. The present review summarizes the mechanisms of mitochondria in chronic neuroinflammatory diseases and the current treatment approaches that target mitochondrial dysfunction in these diseases.

Keywords:  Alzheimer's disease; Parkinson's disease; chronic neuroinflammation; epilepsy; mitochondrial dysfunction; multiple sclerosis; neurodegeneration

DOI:  https://doi.org/10.3892/ijmm.2024.5371
bioRxiv. 2024 Mar 21. pii: 2024.03.21.586175. [Epub ahead of print]

PLD3 and PLD4 synthesize S,S -BMP, a key phospholipid enabling lipid degradation in lysosomes.

Shubham Singh, Ulrich Dransfeld, Yohannes Ambaw, Joshua Lopez-Scarim, Robert V Farese, Tobias C Walther.

Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, in particular gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in the S (rather than the R ) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucial S,S- stereochemistry is achieved is unknown. Here we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomal S,S- BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reaction in vitro . Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including Alzheimer's disease risk, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S- BMP, a crucial lipid for maintaining brain health.

DOI: https://doi.org/10.1101/2024.03.21.586175
Mol Biol Rep. 2024 Apr 05. 51(1): 480

Mitochondrial dysfunction in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome: prospect use of antioxidants and mitochondrial nutrients.

Giovanni Pagano, Alex Lyakhovich, Federico V Pallardó, Luca Tiano, Adriana Zatterale, Marco Trifuoggi.

  Fragile X syndrome (FXS) is a genetic disorder characterized by mutation in the FMR1 gene, leading to the absence or reduced levels of fragile X Messenger Ribonucleoprotein 1 (FMRP). This results in neurodevelopmental deficits, including autistic spectrum conditions. On the other hand, Fragile X-associated tremor/ataxia syndrome (FXTAS) is a distinct disorder caused by the premutation in the FMR1 gene. FXTAS is associated with elevated levels of FMR1 mRNA, leading to neurodegenerative manifestations such as tremors and ataxia.Mounting evidence suggests a link between both syndromes and mitochondrial dysfunction (MDF). In this minireview, we critically examine the intricate relationship between FXS, FXTAS, and MDF, focusing on potential therapeutic avenues to counteract or mitigate their adverse effects. Specifically, we explore the role of mitochondrial cofactors and antioxidants, with a particular emphasis on alpha-lipoic acid (ALA), carnitine (CARN) and Coenzyme Q10 (CoQ10). Findings from this review will contribute to a deeper understanding of these disorders and foster novel therapeutic strategies to enhance patient outcomes.

Keywords:  Alpha-lipoic acid; Carnitine; Coenzyme Q10; Fragile X syndrome (FXS;FXTAS); Mitochondrion

DOI:  https://doi.org/10.1007/s11033-024-09415-7
J Neuroinflammation. 2024 Apr 02. 21(1): 81

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

Min Wang, Tian Tian, Hong Zhou, Si-Yuan Jiang, Ying-Ying Jiao, Zhu Zhu, Jiang Xia, Jian-Hua Ma, Ren-Hong Du.

   BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD.
RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration.
CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

Keywords:  Astrocyte senescence; Metformin; Mitofusin 2; Parkinson’s disease; cGAS-STING

DOI:  https://doi.org/10.1186/s12974-024-03072-0
J Neurosci. 2024 Apr 03. pii: e2215232024. [Epub ahead of print]

TSG-6 mediated extracellular matrix modifications regulate hypoxic-ischemic brain injury.

Taasin Srivastava, Hung Nguyen, Gage Haden, Parham Diba, Steven Sowa, Norah LaNguyen, William Reed-Dustin, Wenbin Zhu, Xi Gong, Edward N Harris, Selva Baltan, Stephen A Back.

Proteoglycans containing link-domains modify the extracellular matrix (ECM) to regulate cellular homeostasis and can also sensitize tissues/organs to injury and stress. Hypoxic-Ischemic (H-I) injury disrupts cellular homeostasis by activating inflammation and attenuating regeneration and repair pathways. In the brain, the main component of the ECM is the glycosaminoglycan (GAG), Hyaluronic Acid (HA), but whether HA modifications of the ECM regulate cellular homeostasis and response to H-I injury is not known. In this report, employing both male and female mice, we demonstrate that link-domain containing proteoglycan, TNFα-stimulated gene-6 (TSG-6), is active in the brain from birth onwards and differentially modifies ECM HA during discrete neurodevelopmental windows. ECM HA modification by TSG-6 enables it to serve as a developmental switch to regulate activity of the Hippo pathway effector protein, Yes Associated Protein 1 (YAP1) in the maturing brain and in response to H-I injury. Mice that lack TSG-6 expression display dysregulated expression of YAP1 targets, excitatory amino acid transporter 1 (EAAT1; GLAST) and 2 (EAAT2; GLT-1). Dysregulation of YAP1 activation in TSG-6-/- mice coincides with age- and sex-dependent sensitization of the brain to H-I injury such that 1-week-old neonates display an anti-inflammatory response in contrast to an enhanced pro-inflammatory injury reaction in 3-month-old adult males but not females. Our findings thus support that a key regulator of age- and sex-dependent H-I injury response in the mouse brain is modulation of the Hippo-YAP1 pathway by TSG-6 dependent ECM modifications.Significance Statement Hypoxic-Ischemic (H-I) injury is a common cause of morbidity and mortality worldwide. Numerous genomic and proteomic screens have identified changes in extracellular matrix (ECM) as the most common finding, yet the downstream mechanistic insights remain obscure. We found that proteoglycan, TNF stimulated gene-6 (TSG-6) dependent ECM modifications regulate the activity of the Hippo pathway effector, the RNA transcription co-activator, Yes Associated Protein 1 (YAP1). Dysregulation of YAP1 activation in TSG-6-/- mice coincided with age- and sex-dependent sensitization of the brain to H-I injury such that neonates displayed an anti-inflammatory response in contrast to an enhanced pro-inflammatory injury reaction in adults. Thus, our findings establish TSG-6-dependent ECM modifications as a key regulator of age- and sex-dependent H-I injury responses.

DOI: https://doi.org/10.1523/JNEUROSCI.2215-23.2024
Front Pharmacol. 2024 ;15 1365051

Sex-specific changes in protein expression of membrane transporters in the brain cortex of 5xFAD mouse model of Alzheimer's disease.

Elena Puris, Liudmila Saveleva, Seppo Auriola, Mikko Gynther, Katja M Kanninen, Gert Fricker.

  Membrane transporters playing an important role in the passage of drugs, metabolites and nutrients across the membranes of the brain cells have been shown to be involved in pathogenesis of Alzheimer's disease (AD). However, little is known about sex-specific changes in transporter protein expression at the brain in AD. Here, we investigated sex-specific alterations in protein expression of three ATP-binding cassette (ABC) and five solute carriers (SLC) transporters in the prefrontal cortex of a commonly used model of familial AD (FAD), 5xFAD mice. Sensitive liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomic analysis was applied for absolute quantification of transporter protein expression. We compared the changes in transporter protein expressions in 7-month-old male and female 5xFAD mice versus sex-matched wild-type mice. The study revealed a significant sex-specific increase in protein expression of ABCC1 (p = 0.007) only in male 5xFAD mice as compared to sex-matched wild-type animals. In addition, the increased protein expression of glucose transporter 1 (p = 0.01), 4F2 cell-surface antigen heavy chain (p = 0.01) and long-chain fatty acid transport protein 1 (p = 0.02) were found only in female 5xFAD mice as compared to sex-matched wild-type animals. Finally, protein expression of alanine/serine/cysteine/threonine transporter 1 was upregulated in both male (p = 0.02) and female (p = 0.002) 5xFAD mice. The study provides important information about sex-specific changes in brain cortical transporter expression in 5xFAD mice, which will facilitate drug development of therapeutic strategies for AD targeting these transporters and drug delivery research.

Keywords:  5XFAD mice; Alzheimer’s disease; age; animal model; brain; membrane transporters; sex

DOI:  https://doi.org/10.3389/fphar.2024.1365051
J Gerontol A Biol Sci Med Sci. 2024 Apr 02. pii: glae088. [Epub ahead of print]

Inhibition of DAPK3 suppresses radiation-induced cellular senescence by activation of a PGC1α-dependent metabolism pathway in brain endothelial cells.

Ji-Eun Park, Jeong Woo Park, Myong-Kyu Sim, So Ra Kim, Kwang Seok Kim.

  In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and ROS. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism-associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.

Keywords:  DAPK3; brain aging; cellular senescence; endothelial cell; metabolic decline

DOI:  https://doi.org/10.1093/gerona/glae088
Eur J Neurol. 2024 Apr 04. e16275

Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.

Michelangelo Mancuso, Maria T Papadopoulou, Yi Shiau Ng, Anna Ardissone, Marcello Bellusci, Enrico Bertini, Lidia Di Vito, Teresinha Evangelista, Carmen Fons, Omar Hikmat, Rita Horvath, Thomas Klopstock, Cornelia Kornblum, Costanza Lamperti, Laura Licchetta, Maria Judit Molnar, Kristin N Varhaug, Mar O'Callaghan, Ronit M Pressler, Manuel Schiff, Serenella Servidei, Nora Szabo, Gráinne S Gorman, J Helen Cross, Shamima Rahman.

   BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy.
METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement.
RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted.
CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Keywords:  consensus; epilepsy; management; mitochondrial diseases; recommendations

DOI:  https://doi.org/10.1111/ene.16275
Adv Redox Res. 2024 Apr;pii: 100097. [Epub ahead of print]10

Sex-specific antioxidant biomarker depletion in patients with a history of mild traumatic brain injury.

Lilia A Koza, Allison N Grossberg, McKensey Bishop, Chad Prusmack, Daniel A Linseman.

  Individuals with a history of mild traumatic brain injury (mTBI) are at an increased risk for neurodegenerative disease, suggesting that intrinsic neuroprotective mechanisms, such as the endogenous antioxidant reservoir, may be depleted long-term after mTBI. Here, we retrospectively analyzed symptoms and blood antioxidants in patients with a history of mTBI who presented to Resilience Code, a sports medicine clinic in Colorado. Significant decreases in alpha-tocopherol, selenium, linoleic acid, taurine, docosahexaenoic acid, and total omega-3 were measured in the total mTBI population versus controls. Male mTBI patients showed depletion of a larger array of antioxidants than females. Patients with a history of mTBI also reported significantly worsened emotional, energy, head, and cognitive symptoms, with males displaying more extensive symptomology. Multiple or chronic mTBI patients had worsened symptoms than single or acute/subchronic mTBI patients, respectively. Finally, male mTBI patients with the largest reductions in polyunsaturated fatty acids (PUFAs) displayed worse symptomology than male mTBI patients with less depletion of this antioxidant reservoir. These results demonstrate that antioxidant depletion persists in patients with a history of mTBI and these deficits are sex-specific and associated with worsened symptomology. Furthermore, supplementation with specific antioxidants, like PUFAs, may diminish symptom severity in patients suffering from chronic effects of mTBI.

Keywords:  Antioxidants; Biomarkers; Polyunsaturated fatty acids; Symptomology; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.arres.2024.100097
Antioxid Redox Signal. 2024 Apr 04.

Targeting mitochondrial oxidative stress to protect against preterm birth and fetal brain injury via Nrf2 induction.

Chaolu Chen, Shuaiying Zhu, Tiantian Fu, Yanmin Chen, Long Bai, Danqing Chen.

AIMS: Preterm birth, recognized as delivery before 37 weeks of gestation, is a multifactorial syndrome characterizing as the main cause of neonatal mortality. Reactive oxygen species (ROS) have been identified as proinﬂammatory factors to cause placental inflammation, thereby resulting in several pregnancy outcomes. To date, limited knowledge regarding the underlying mechanisms of ROS-induced preterm birth has been reported. Here, we aimed to investigate the role of oxidative stress in preterm birth and the protective effects of mitochondria-targeted antioxidant MitoTEMPO (MT) on preterm labor and offspring mice.
RESULTS: Here, we found that preterm placentas had abnormal mitochondrial function, oxidative stress and inflammatory response. In the LPS-induced preterm birth mouse model, MT inhibited preterm birth by ameliorating maternal oxidative stress and inflammation, especially in placentas, thus improving placental function to maintain pregnancy. Antenatal administration of MT prevented LPS-induced fetal brain damage in acute phase and improved long-term neurodevelopmental impairments. Furthermore, our in vitro investigations validated that MT retarded the ROS accumulation and inﬂammatory response in LPS-stimulated trophoblast cells by promoting Keap1 degradation and subsequently activating Nrf2. By inhibiting Nrf2 activation, we discovered that the anti-inflammation and protective characteristics of MT were Nrf2/ARE pathway-dependent.
INNOVATION AND CONCLUSION: MT inhibited preterm birth and fetal brain injury by inhibiting maternal inflammation and improving placental function through Keap1/Nrf2/ARE signaling pathway. Our findings provide a novel therapeutic strategy for preterm birth.

DOI: https://doi.org/10.1089/ars.2023.0382
Eur J Pharmacol. 2024 Mar 31. pii: S0014-2999(24)00227-9. [Epub ahead of print]971 176539

Metabolomics analysis revealed the neuroprotective role of 2-phosphoglyceric acid in hypoxic-ischemic brain damage through GPX4/ACSL4 axis regulation.

Haocong Chen, Yimingjiang Wusiman, Jing Zhao, Wenyi Zhang, Wenjuan Liu, Shuyan Wang, Gang Qian, Guangming Zhang, Meini Le, Xiaohua Dong.

  Hypoxic-ischemic brain damage (HIBD) is a cerebral injury resulting from the combination of ischemia and hypoxia in neonatal brain tissue. Presently, there exists no efficacious remedy for HIBD. A mounting body of evidence indicates that dynamic metabolites formed during metabolic procedures assume a vital role in neuronal maturation and recuperation. However, it remains unclear whether any endogenous metabolites are involved in the pathogenesis of HIBD. Here, an untargeted metabolomics analysis was conducted by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (GC/LC-MS) in OGD/R (oxygen-glucose deprivation/reoxygenation)-induced HT-22 cells. We observed that ferroptosis signaling plays an essential role in HI-induced neuronal injury. Interestingly, we also found that the differentially expressed metabolite, 2-phosphoglyceric acid, significantly improved the neuronal cell survival of OGD/R HT-22 cells by inhibiting ferroptosis. Moreover, 2-phosphoglyceric acid effectively rescued the cell activity of HT-22 cells treated with the ferroptosis inducer RSL-3. Furthermore, 2-phosphoglyceric acid alleviated cerebral infarction and reduced HIBD-induced neuronal cell loss of the central nervous system in neonatal rats by regulating GPX4 expression. Taken together, we found that 2-phosphoglyceric acid, which was downregulated in HT-22 cells induced by OGD/R, exerted neuronal protective effects on OGD/R-treated HT-22 cells and HIBD-induced neonatal rats by inhibiting hypoxic-ischemic-induced ferroptosis through the regulation of the GPX4/ACSL4 axis.

Keywords:  2-Phosphoglyceric acid; Ferroptosis; Hypoxic-ischemic brain damage; Metabolomics; OGD/R injury

DOI:  https://doi.org/10.1016/j.ejphar.2024.176539
J Neurosci. 2024 Apr 02. pii: e1563232024. [Epub ahead of print]

Imbalance in glucose metabolism regulates the transition of microglia from homeostasis to Disease Associated Microglia stage 1.

Yuxi Liu, Witty Kwok, Hyojung Yoon, Jae Cheon Ryu, Patrick Stevens, Tara R Hawkinson, Cameron J Shedlock, Roberto A Ribas, Terrymar Medina, Shannon B Keohane, Douglas Scharre, Lei Bruschweiler-Li, Rafael Bruschweiler, Alban Gaultier, Karl Obrietan, Ramon C Sun, Sung Ok Yoon.

Microglia undergo two-stage activation in neurodegenerative diseases, known as disease-associated microglia (DAM). TREM2 mediates the DAM2 stage transition, but what regulates the first DAM1 stage transition is unknown. We report that glucose dyshomeostasis inhibits DAM1 activation, and PKM2 plays a role. As in tumors, PKM2 was aberrantly elevated in both male and female human AD brains, but unlike in tumors, it is expressed as active tetramers, as well as among TREM2+ microglia surrounding plaques in 5XFAD male and female mice. snRNAseq analyses of microglia without Pkm2 in 5XFAD mice revealed significant increases in DAM1 markers in a distinct 'metabolic' cluster, which is enriched in genes for glucose metabolism, DAM1, and AD risk. 5XFAD mice incidentally exhibited a significant reduction in amyloid pathology without microglial Pkm2 Surprisingly, microglia in 5XFAD without Pkm2 exhibited increases in glycolysis and spare respiratory capacity, which correlated with restoration of mitochondrial cristae alterations. In addition, in situ spatial metabolomics of plaque-bearing microglia revealed an increase in respiratory activity. These results together suggest that it is not only glycolytic but also respiratory inputs that are critical to the development of DAM signatures in 5XFAD mice.Significance Statement Although reduced glucose uptake in the brain has been recognized as one of the earliest pathological events that accompany Alzheimer's disease (AD), it has not been clear whether this was due to a brain-wide defect in glucose metabolism or a dysfunction in a particular cell type. Our data suggest that dysregulation of metabolic homeostasis in microglia is critical for global AD pathology in a mouse model. Upon restoring glucose metabolism in microglia genetically, AD pathology is attenuated with a concomitant increase in DAM genes, especially DAM1 genes. These results suggest that this increase in DAM gene expression is protective against AD pathology, and glucose dyshomeostasis is a trigger to inhibit expression of protective DAM genes in AD.

DOI: https://doi.org/10.1523/JNEUROSCI.1563-23.2024
Neuropharmacology. 2024 Apr 01. pii: S0028-3908(24)00109-6. [Epub ahead of print] 109940

Pharmacological blockade of 2-AG degradation ameliorates clinical, neuroinflammatory and synaptic alterations in experimental autoimmune encephalomyelitis.

Livia Guadalupi, Georgia Mandolesi, Valentina Vanni, Sara Balletta, Silvia Caioli, Anto Pavlovic, Francesca De Vito, Diego Fresegna, Krizia Sanna, Laura Vitiello, Monica Nencini, Alice Tartacca, Fabrizio Mariani, Valentina Rovella, Sven Schippling, Iris Ruf, Ludovic Collin, Diego Centonze, Alessandra Musella.

  The endocannabinoid system (ECS) is critically involved in the pathophysiology of Multiple Sclerosis (MS), a neuroinflammatory and neurodegenerative disease of the central nervous system (CNS). Over the past decade, researchers have extensively studied the neuroprotective and anti-inflammatory effects of the ECS. Inhibiting the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) has emerged as a promising strategy to mitigate brain damage in MS. In this study, we investigated the effects of a novel reversible MAGL inhibitor (MAGLi 432) on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. We assessed its implications on motor disability, neuroinflammation, and synaptic dysfunction. Systemic in vivo treatment with MAGLi 432 resulted in a less severe EAE disease, accompanied by increased 2-AG levels and decreased levels of arachidonic acid (AA) and prostaglandins (PGs) in the brain. Additionally, MAGLi 432 reduced both astrogliosis and microgliosis, as evidenced by decreased microglia/macrophage density and a less reactive morphology. Flow cytometry analysis further revealed fewer infiltrating CD45+ and CD3+ cells in the brains of MAGLi 432-treated EAE mice. Finally, MAGLi treatment counteracted the striatal synaptic hyperexcitability promoted by EAE neuroinflammation. In conclusion, MAGL inhibition significantly ameliorated EAE clinical disability and striatal inflammatory synaptopathy through potent anti-inflammatory effects. These findings provide new mechanistic insights into the neuroprotective role of the ECS during neuroinflammation and highlight the therapeutic potential of MAGLi-based drugs in mitigating MS-related inflammatory and neurodegenerative brain damage.

Keywords:  Endocannabinoid; Excitotoxicity; Microglia; Monoacylglycerol lipase (MAGL); Multiple sclerosis (MS); Neuroinflammation; Synaptic transmission

DOI:  https://doi.org/10.1016/j.neuropharm.2024.109940
Neurotherapeutics. 2024 Apr 04. pii: S1878-7479(24)00041-2. [Epub ahead of print] e00355

Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.

Hyeyoon Eo, Shin-Hye Yu, Yujin Choi, Yujin Kim, Young Cheol Kang, Hanbyeol Lee, Jin Hee Kim, Kyuboem Han, Hong Kyu Lee, Mi-Yoon Chang, Myung Sook Oh, Chun-Hyung Kim.

  Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.

Keywords:  Mitochondria; Mitotherapy; Neuroprotective; Parkinson's disease; Transplantation

DOI:  https://doi.org/10.1016/j.neurot.2024.e00355
Ther Adv Chronic Dis. 2024 ;15 20406223241229855

Brain functional and structural changes in diabetic children. How can intellectual development be optimized in type 1 diabetes?

Maia Stanisławska-Kubiak, Katarzyna Anna Majewska, Agata Krasińska, Paulina Wais, Dominik Majewski, Ewa Mojs, Andrzej Kȩdzia.

  The neuropsychological functioning of people with type 1 diabetes (T1D) is of key importance to the effectiveness of the therapy, which, in its complexity, requires a great deal of knowledge, attention, and commitment. Intellectual limitations make it difficult to achieve the optimal metabolic balance, and a lack of this alignment can contribute to the further deterioration of cognitive functions. The aim of this study was to provide a narrative review of the current state of knowledge regarding the influence of diabetes on brain structure and functions during childhood and also to present possible actions to optimize intellectual development in children with T1D. Scopus, PubMed, and Web of Science databases were searched for relevant literature using selected keywords. The results were summarized using a narrative synthesis. Disturbances in glucose metabolism during childhood may have a lasting negative effect on the development of the brain and related cognitive functions. To optimize intellectual development in children with diabetes, it is essential to prevent disorders of the central nervous system by maintaining peri-normal glycemic levels. Based on the performed literature review, it seems necessary to take additional actions, including repeated neuropsychological evaluation with early detection of any cognitive dysfunctions, followed by the development of individual management strategies and the training of appropriate skills, together with complex, multidirectional environmental support.

Keywords:  brain; children; cognitive functions; type 1 diabetes

DOI:  https://doi.org/10.1177/20406223241229855