bims-medebr 2024-03-17 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–03–17
29 papers selected by
Regina F. Fernández, Johns Hopkins University

Thermodynamic Analysis to Evaluate the Effect of Diet on Brain Glucose Metabolism: The Case of Fish Oil.
Redox imbalance and metabolic defects in the context of Alzheimer disease.
Cerebral Glucose Metabolism following TBI: Changes in Plasma Glucose, Glucose Transport and Alternative Pathways of Glycolysis-A Translational Narrative Review.
Cholesterol modulation of interactions between psychostimulants and dopamine transporters.
Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.
Repeatability of deuterium metabolic imaging of healthy volunteers at 3 T.
Metabolic Diaschisis in Mild Traumatic Brain Injury.
Co-registration of MALDI-MSI and histology demonstrates gangliosides co-localize with amyloid beta plaques in Alzheimer's disease.
Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa.
Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.
Pomalidomide Improves Motor Behavioral Deficits and Protects Cerebral Cortex and Striatum Against Neurodegeneration Through a Reduction of Oxidative/Nitrosative Damages and Neuroinflammation After Traumatic Brain Injury.
A Vascular-Centric Approach to Autism Spectrum Disorders.
Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration.
Investigating a Novel Neurodegenerative Disease Toxic Mechanism Involving Lipid Binding Specificity of Amyloid Oligomers.
Metabolic coupling between glutamate and N-acetylaspartate in the human brain.
Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases.
Long term follow-up in GAMT deficiency - Correlation of therapy regimen, biochemical and in vivo brain proton MR spectroscopy data.
Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex.
Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson's Disease and Parkinsonism-Dementia of Guam.
Changes in the Glutamate/GABA System in the Hippocampus of Rats with Age and during Alzheimer's Disease Signs Development.
APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12.
Evidence of brain metabolism redistribution from neocortex to primitive brain structures in early acute COVID-19 respiratory syndrome.
13 C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs.
Integrative brain omics approach reveals key role for sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.
Mitochondrial complex I activity in microglia sustains neuroinflammation.
Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.
APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.
Activity-dependent mitochondrial ROS signaling regulates recruitment of glutamate receptors to synapses.

Nutrients. 2024 Feb 24. pii: 631. [Epub ahead of print]16(5):

Thermodynamic Analysis to Evaluate the Effect of Diet on Brain Glucose Metabolism: The Case of Fish Oil.

Cennet Yildiz, Isabel Medina.

  Inefficient glucose metabolism and decreased ATP production in the brain are linked to ageing, cognitive decline, and neurodegenerative diseases (NDDs). This study employed thermodynamic analysis to assess the effect of fish oil supplementation on glucose metabolism in ageing brains. Data from previous studies on glucose metabolism in the aged human brain and grey mouse lemur brains were examined. The results demonstrated that Omega-3 fish oil supplementation in grey mouse lemurs increased entropy generation and decreased Gibbs free energy across all brain regions. Specifically, there was a 47.4% increase in entropy generation and a 47.4 decrease in Gibbs free energy in the whole brain, indicating improved metabolic efficiency. In the human model, looking at the specific brain regions, supplementation with Omega-3 polyunsaturated fatty acids (n-3 PUFAs) reduced the entropy generation difference between elderly and young individuals in the cerebellum and particular parts of the brain cortex, namely the anterior cingulate and occipital lobe, with 100%, 14.29%, and 20% reductions, respectively. The Gibbs free energy difference was reduced only in the anterior cingulate by 60.64%. This research underscores that the application of thermodynamics is a comparable and powerful tool in comprehending the dynamics and metabolic intricacies within the brain.

Keywords:  Gibbs free energy; brain ageing; brain glucose metabolism; entropy; fish oil supplementation; n-3 PUFAs

DOI:  https://doi.org/10.3390/nu16050631
FEBS Lett. 2024 Mar 12.

Redox imbalance and metabolic defects in the context of Alzheimer disease.

Fabio Di Domenico, Chiara Lanzillotta, Marzia Perluigi.

  Redox reactions play a critical role for intracellular processes, including pathways involved in metabolism and signaling. Reactive oxygen species (ROS) act either as second messengers or generators of protein modifications, fundamental mechanisms for signal transduction. Disturbance of redox homeostasis is associated with many disorders. Among these, Alzheimer's disease is a neurodegenerative pathology that presents hallmarks of oxidative damage such as increased ROS production, decreased activity of antioxidant enzymes, oxidative modifications of macromolecules, and changes in mitochondrial homeostasis. Interestingly, alteration of redox homeostasis is closely associated with defects of energy metabolism, involving both carbohydrates and lipids, the major energy fuels for the cell. As the brain relies exclusively on glucose metabolism, defects of glucose utilization represent a harmful event for the brain. During aging, a progressive perturbation of energy metabolism occurs resulting in brain hypometabolism. This condition contributes to increase neuronal cell vulnerability ultimately resulting in cognitive impairment. The current review discusses the crosstalk between alteration of redox homeostasis and brain energy defects that seems to act in concert in promoting Alzheimer's neurodegeneration.

Keywords:  Alzheimer disease; down syndrome; energy metabolism; insulin resistance; mitochondria; oxidative stress; redox homeostasis

DOI:  https://doi.org/10.1002/1873-3468.14840
Int J Mol Sci. 2024 Feb 21. pii: 2513. [Epub ahead of print]25(5):

Cerebral Glucose Metabolism following TBI: Changes in Plasma Glucose, Glucose Transport and Alternative Pathways of Glycolysis-A Translational Narrative Review.

Annerixt Gribnau, Mark L van Zuylen, Jonathan P Coles, Mark P Plummer, Henning Hermanns, Jeroen Hermanides.

  Traumatic brain injury (TBI) is a major public health concern with significant consequences across various domains. Following the primary event, secondary injuries compound the outcome after TBI, with disrupted glucose metabolism emerging as a relevant factor. This narrative review summarises the existing literature on post-TBI alterations in glucose metabolism. After TBI, the brain undergoes dynamic changes in brain glucose transport, including alterations in glucose transporters and kinetics, and disruptions in the blood-brain barrier (BBB). In addition, cerebral glucose metabolism transitions from a phase of hyperglycolysis to hypometabolism, with upregulation of alternative pathways of glycolysis. Future research should further explore optimal, and possibly personalised, glycaemic control targets in TBI patients, with GLP-1 analogues as promising therapeutic candidates. Furthermore, a more fundamental understanding of alterations in the activation of various pathways, such as the polyol and lactate pathway, could hold the key to improving outcomes following TBI.

Keywords:  cerebral glucose metabolism; hyperglycaemia; traumatic brain injury

DOI:  https://doi.org/10.3390/ijms25052513
Adv Pharmacol. 2024 ;pii: S1054-3589(23)00050-9. [Epub ahead of print]99 35-59

Cholesterol modulation of interactions between psychostimulants and dopamine transporters.

Rong Chen.

  The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse. Cholesterol interacts with sphingolipids forming lipid raft microdomains on the membrane. These cholesterol-rich lipid raft microdomains serve to recruit and assemble other lipids and proteins to initiate signal transduction. There are two spatially and functionally distinct populations of the DAT segregated by cholesterol-rich lipid raft microdomains and cholesterol-scarce non-raft microdomains on the plasma membrane. These two DAT populations are differentially regulated by DAT blockers (e.g. cocaine), substrates (e.g. amphetamine), and protein kinase C providing distinct cholesterol-dependent modulation of dopamine uptake and efflux. In this chapter, we summarize the impact of depletion and addition of membrane cholesterol on DAT conformational changes between the outward-facing and the inward-facing states, lipid raft-associated DAT localization, basal and induced DAT internalization, and DAT function. In particular, we focus on how the interactions of the DAT with cocaine and amphetamine are influenced by membrane cholesterol. Lastly, we discuss the therapeutic potential of cholesterol-modifying drugs as a new avenue to normalize DAT function and dopamine transmission in patients with psychostimulant use disorder.

Keywords:  Cholesterol; Dopamine efflux; Dopamine transporters; Dopamine uptake; Lipid rafts; Psychostimulants

DOI:  https://doi.org/10.1016/bs.apha.2023.09.004
Cells. 2024 Feb 27. pii: 410. [Epub ahead of print]13(5):

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.

Kuldeep Tripathi, Dorit Ben-Shachar.

  Mitochondria, the energy suppliers of the cells, play a central role in a variety of cellular processes essential for survival or leading to cell death. Consequently, mitochondrial dysfunction is implicated in numerous general and CNS disorders. The clinical manifestations of mitochondrial dysfunction include metabolic disorders, dysfunction of the immune system, tumorigenesis, and neuronal and behavioral abnormalities. In this review, we focus on the mitochondrial role in the CNS, which has unique characteristics and is therefore highly dependent on the mitochondria. First, we review the role of mitochondria in neuronal development, synaptogenesis, plasticity, and behavior as well as their adaptation to the intricate connections between the different cell types in the brain. Then, we review the sparse knowledge of the mechanisms of exogenous mitochondrial uptake and describe attempts to determine their half-life and transplantation long-term effects on neuronal sprouting, cellular proteome, and behavior. We further discuss the potential of mitochondrial transplantation to serve as a tool to study the causal link between mitochondria and neuronal activity and behavior. Next, we describe mitochondrial transplantation's therapeutic potential in various CNS disorders. Finally, we discuss the basic and reverse-translation challenges of this approach that currently hinder the clinical use of mitochondrial transplantation.

Keywords:  CNS; mitochondria; mitochondria and behavior; mitochondrial transplantation; neural development and function; neuropsychiatric disorders

DOI:  https://doi.org/10.3390/cells13050410
Eur Radiol Exp. 2024 Mar 13. 8(1): 44

Repeatability of deuterium metabolic imaging of healthy volunteers at 3 T.

Nikolaj Bøgh, Michael Vaeggemose, Rolf F Schulte, Esben S S Hansen, Christoffer Laustsen.

   BACKGROUND: Magnetic resonance (MR) imaging of deuterated glucose, termed deuterium metabolic imaging (DMI), is emerging as a biomarker of pathway-specific glucose metabolism in tumors. DMI is being studied as a useful marker of treatment response in a scan-rescan scenario. This study aims to evaluate the repeatability of brain DMI.
METHODS: A repeatability study was performed in healthy volunteers from December 2022 to March 2023. The participants consumed 75 g of [6,6'-2H2]glucose. The delivery of 2H-glucose to the brain and its conversion to 2H-glutamine + glutamate, 2H-lactate, and 2H-water DMI was imaged at baseline and at 30, 70, and 120 min. DMI was performed using MR spectroscopic imaging on a 3-T system equipped with a 1H/2H-tuned head coil. Coefficients of variation (CoV) were computed for estimation of repeatability and between-subject variability. In a set of exploratory analyses, the variability effects of region, processing, and normalization were estimated.
RESULTS: Six male participants were recruited, aged 34 ± 6.5 years (mean ± standard deviation). There was 42 ± 2.7 days between sessions. Whole-brain levels of glutamine + glutamate, lactate, and glucose increased to 3.22 ± 0.4 mM, 1.55 ± 0.3 mM, and 3 ± 0.7 mM, respectively. The best signal-to-noise ratio and repeatability was obtained at the 120-min timepoint. Here, the within-subject whole-brain CoVs were -10% for all metabolites, while the between-subject CoVs were -20%.
CONCLUSIONS: DMI of glucose and its downstream metabolites is feasible and repeatable on a clinical 3 T system.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT05402566 , registered the 25th of May 2022.
RELEVANCE STATEMENT: Brain deuterium metabolic imaging of healthy volunteers is repeatable and feasible at clinical field strengths, enabling the study of shifts in tumor metabolism associated with treatment response.
KEY POINTS: • Deuterium metabolic imaging is an emerging tumor biomarker with unknown repeatability. • The repeatability of deuterium metabolic imaging is on par with FDG-PET. • The study of deuterium metabolic imaging in clinical populations is feasible.

Keywords:  Biomarkers (tumor); Brain; Deuterium; Glucose; Magnetic resonance imaging

DOI:  https://doi.org/10.1186/s41747-024-00426-4
J Neurotrauma. 2024 Mar 14.

Metabolic Diaschisis in Mild Traumatic Brain Injury.

Robert Cole Boggs, Lora Talley Watts, Peter T Fox, Geoffrey D Clarke.

  Neurophysiological diaschisis presents in traumatic brain injury (TBI) as functional impairment distant to the lesion site caused by axonal neuroexcitation and deafferentation. Diaschisis studies in TBI models have evaluated acute phase functional and microstructural changes. Here, in vivo biochemical changes and cerebral blood flow (CBF) dynamics following TBI are studied with magnetic resonance. Behavioral assessments, magnetic resonance spectroscopy (MRS), and CBF measurements on rats followed cortical impact TBI. Data were acquired pre-TBI and 1-3 hours, 2-days, 7-days, and 14-days post-TBI. MRS was performed on the ipsilateral and contralateral sides in the cortex, striatum, and thalamus. Metabolites measured by MRS included n-acetyl aspartate (NAA), aspartate (Asp), lactate (Lac), glutathione (GSH), and glutamate (Glu). Lesion volume expanded for 2 days post-TBI and then decreased. Ipsilateral CBF dropped acutely vs. baseline on both sides (-62% ipsilateral, -48% contralateral, p<0.05) but then recovered in cortex, with similar changes in ipsilateral striatum. Metabolic changes vs. baseline included increased Asp (+640% by Day 7 post TBI, p<0.05) and Lac (+140% on Day 2 post TBI, p<0.05) in ipsilateral cortex, while GSH (-67% acutely, p<0.05) and NAA decreased (-50% on Day 2, p<0.05). In contralateral cortex Lac decreased (-73% acutely, p<0.05). ANOVA showed significance for Side (p<0.05), Time after TBI (p<0.05), and interactions (p<0.005) for Asp, GSH, Lac, and NAA. Transient decreases of GSH (-30%, p<0.05, acutely) and NAA (-23% on Day 2, p<0.05) occurred in ipsilateral striatum with reduced GSH (-42%, p<0.005, acutely) in the contralateral striatum. GSH was decreased in ipsilateral thalamus (-59% ipsilateral on Day 2, p<0.05). Delayed increases of total Choline were seen in the contralateral thalamus were noted as well (+21% on Day 7 post TBI, p<0.05). Both CBF and neurometabolite concentration changes occurred remotely from the TBI site, both ipsilaterally and contralaterally. Decreased Lac levels on the contralateral cortex following TBI may be indicative of reduced anaerobic metabolism during the acute phase. The timing and locations of the changes suggest excitatory and inhibitory signaling processes are affecting post-TBI metabolic fluctuations.

Keywords:  BLOOD FLOW; MODELS OF INJURY; MRI SPECTROSCOPY; TRAUMATIC BRAIN INJURY

DOI:  https://doi.org/10.1089/neu.2023.0290
Res Sq. 2024 Feb 27. pii: rs.3.rs-3985371. [Epub ahead of print]

Co-registration of MALDI-MSI and histology demonstrates gangliosides co-localize with amyloid beta plaques in Alzheimer's disease.

Nikita Ollen-Bittle, Shervin Pejhan, Stephen H Pasternak, C Dirk Keene, Qi Zhang, Shawn N Whitehead.

  Alzheimer's disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioural alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have triggered increased exploration of the AD lipidome with lipid dysregulation emerging as a critical player in AD pathogenesis. Gangliosides are a class of glycosphingolipids enriched within the central nervous system. Previous work has suggested a shift in a-series gangliosides from complex (GM1) to simple (GM2 and GM3) species may be related to the development of neurodegenerative disease. Additionally, complex gangliosides with 20 carbon sphingosine chains have been shown to increase in the aging brain. In this study, we utilized matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to interrogate the in situ relationship of a-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1 respectively) in the post-mortem human AD brain. Here, we expanded upon previous literature and demonstrated a significant decrease in the GM1 d20:1:GM1 d18:1 ratio in regions of the dentate gyrus and entorhinal cortex in AD relative to control brain tissue. Then we demonstrated that the MALDI-MSI profile of GM3 co-localizes with histologically confirmed amyloid beta (Aβ) plaques and found a significant increase in both GM1 and GM3 in proximity to Aβ plaques. Collectively these results support past literature and demonstrate a perturbation of the ganglioside profile in AD. Moreover, this work validates a pipeline for MALDI-MSI and classic histological staining in the same tissue sections. This demonstrates feasibility for integrating untargeted mass spectrometry imaging approaches into a digital pathology framework.

Keywords:  Alzheimer’s disease; MALDI-MSI; digital pathology; gangliosides; lipids

DOI:  https://doi.org/10.21203/rs.3.rs-3985371/v1
J Neurochem. 2024 Mar 14.

Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa.

Wyn Firth, Josephine L Robb, Daisy Stewart, Katherine R Pye, Rosemary Bamford, Asami Oguro-Ando, Craig Beall, Kate L J Ellacott.

  The mitochondrial translocator protein 18 kDa (TSPO) has been linked to functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in Leydig cells and microglia indicate that TSPO function may vary between cells depending on their specialized roles. Astrocytes are critical for providing trophic and metabolic support in the brain. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. Relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO-deficient (TSPO-/- ) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed extracellular metabolic flux analyses. We found that TSPO deficiency reduced basal cellular respiration and attenuated the bioenergetic response to glucopenia. Fatty acid oxidation was increased, and lactate production was reduced in TSPO-/- MPAs and U373 cells. Co-immunoprecipitation studies revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a in U373 and MPAs, presenting a mechanism wherein TSPO may regulate FAO in these cells. Compared to TSPO+/+ cells, in TSPO-/- MPAs we observed attenuated tumor necrosis factor release following 3 h lipopolysaccharide (LPS) stimulation, which was enhanced at 24 h post-LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility, TSPO deficiency does not appear to modulate the metabolic response of MPAs to inflammation, at least in response to the model used in this study.

Keywords:  TSPO; astrocyte; cytokine release; fatty acid oxidation; inflammation; metabolism

DOI:  https://doi.org/10.1111/jnc.16089
Sci Adv. 2024 Mar 15. 10(11): eadm8600

Molecular imaging of tumor metabolism: Insight from pyruvate- and glucose-based deuterium MRI studies.

Elton T Montrazi, Keren Sasson, Lilach Agemy, Avigdor Scherz, Lucio Frydman.

Cancer diagnosis by metabolic MRI proposes to follow the fate of glycolytic precursors such as pyruvate or glucose, and their in vivo conversion into lactate. This study compares the 2H MRI outlooks afforded by these metabolites when targeting a pancreatic cancer model. Exogenously injected [3,3',3″-2H3]-pyruvate was visible only briefly; it generated a deuterated lactate signal throughout the body that faded after ~5 min, showing a minor concentration bias at the rims of the tumors. [6,6'-2H2]-glucose by contrast originated a lactate signal that localized clearly within the tumors, persisting for over an hour. Investigations alternating deuterated and nondeuterated glucose injections revealed correlations between the lactate generation and the glucose available at the tumor, evidencing a continuous and avid glucose consumption generating well-localized lactate signatures as driven by the Warburg effect. This is by contrast to the transient and more promiscuous pyruvate-to-lactate transformation, which seemed subject to transporter and kinetics effects. The consequences of these observations within metabolic MRI are briefly discussed.

DOI: https://doi.org/10.1126/sciadv.adm8600
Cell Transplant. 2024 Jan-Dec;33:33 9636897241237049

Pomalidomide Improves Motor Behavioral Deficits and Protects Cerebral Cortex and Striatum Against Neurodegeneration Through a Reduction of Oxidative/Nitrosative Damages and Neuroinflammation After Traumatic Brain Injury.

Ya-Ni Huang, Nigel H Greig, Pen-Sen Huang, Yung-Hsiao Chiang, Alan Hoffer, Chih-Hao Yang, David Tweedie, Ying Chen, Ju-Chi Ou, Jia-Yi Wang.

  Neuronal damage resulting from traumatic brain injury (TBI) causes disruption of neuronal projections and neurotransmission that contribute to behavioral deficits. Cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an early event following TBI. ROS often damage DNA, lipids, proteins, and carbohydrates while RNS attack proteins. The products of lipid peroxidation 4-hydroxynonenal (4-HNE) and protein nitration 3-nitrotyrosine (3-NT) are often used as indicators of oxidative and nitrosative damages, respectively. Increasing evidence has shown that striatum is vulnerable to damage from TBI with a disturbed dopamine neurotransmission. TBI results in neurodegeneration, oxidative stress, neuroinflammation, neuronal apoptosis, and autophagy in the striatum and contribute to motor or behavioral deficits. Pomalidomide (Pom) is a Food and Drug Administration (FDA)-approved immunomodulatory drug clinically used in treating multiple myeloma. We previously showed that Pom reduces neuroinflammation and neuronal death induced by TBI in rat cerebral cortex. Here, we further compared the effects of Pom in cortex and striatum focusing on neurodegeneration, oxidative and nitrosative damages, as well as neuroinflammation following TBI. Sprague-Dawley rats subjected to a controlled cortical impact were used as the animal model of TBI. Systemic administration of Pom (0.5 mg/kg, intravenous [i.v.]) at 5 h post-injury alleviated motor behavioral deficits, contusion volume at 24 h after TBI. Pom alleviated TBI-induced neurodegeneration stained by Fluoro-Jade C in both cortex and striatum. Notably, Pom treatment reduces oxidative and nitrosative damages in cortex and striatum and is more efficacious in striatum (93% reduction in 4-HNE-positive and 84% reduction in 3-NT-positive neurons) than in cerebral cortex (42% reduction in 4-HNE-positive and 55% reduction in 3-NT-positive neurons). In addition, Pom attenuated microgliosis, astrogliosis, and elevations of proinflammatory cytokines in cortical and striatal tissue. We conclude that Pom may contribute to improved motor behavioral outcomes after TBI through targeting oxidative/nitrosative damages and neuroinflammation.

Keywords:  motor behavioral deficits; neurodegeneration; oxidative/nitrosative damages; pomalidomide; traumatic brain injury

DOI:  https://doi.org/10.1177/09636897241237049
Neurosci Insights. 2024 ;19 26331055241235921

A Vascular-Centric Approach to Autism Spectrum Disorders.

Julie Ouellette, Elizabeth E Crouch, Jean-Luc Morel, Vanessa Coelho-Santos, Baptiste Lacoste.

  Brain development and function are highly reliant on adequate establishment and maintenance of vascular networks. Early impairments in vascular health can impact brain maturation and energy metabolism, which may lead to neurodevelopmental anomalies. Our recent work not only provides novel insights into the development of cerebrovascular networks but also emphasizes the importance of their well-being for proper brain maturation. In particular, we have demonstrated that endothelial dysfunction in autism spectrum disorders (ASD) mouse models is causally related to altered behavior and brain metabolism. In the prenatal human brain, vascular cells change metabolic states in the second trimester. Such findings highlight the need to identify new cellular and molecular players in neurodevelopmental disorders, raising awareness about the importance of a healthy vasculature for brain development. It is thus essential to shift the mostly neuronal point of view in research on ASD and other neurodevelopmental disorders to also include vascular and metabolic features.

Keywords:  Autism; angiogenesis; cerebrovascular; endothelium; metabolism; neurodevelopment

DOI:  https://doi.org/10.1177/26331055241235921
Int J Mol Sci. 2024 Mar 06. pii: 3050. [Epub ahead of print]25(5):

Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration.

Marta Sidoryk-Węgrzynowicz, Kamil Adamiak, Lidia Strużyńska.

  Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood-brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate-glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders.

Keywords:  astrocyte–neuron integrity; glutamate transporters; glutamate–glutamine cycle; glutamine transporters; tau-dependent neurodegeneration

DOI:  https://doi.org/10.3390/ijms25053050
ACS Chem Neurosci. 2024 Mar 15.

Investigating a Novel Neurodegenerative Disease Toxic Mechanism Involving Lipid Binding Specificity of Amyloid Oligomers.

Sarah S Hirschbeck, Edward T Lindberg, Joshua H Jang, MaKenna R Jacob, Kristi L Lazar Cantrell, Thanh D Do.

  Exploring the mechanisms underlying the toxicity of amyloid oligomers (AOs) presents a significant opportunity for discovering cures and developing treatments for neurodegenerative diseases. Recently, using a combination of ion mobility spectrometry-mass spectrometry (IMS-MS) and X-ray crystallography (XRC), we showed that the peptide KVKVLWDVIEV, which is the G95W mutant of αB-Crystallin (90-100) and abbreviated as G6W, self-assembles up to a dodecamer that structurally resembles lipid transport proteins. The glycine to tryptophan mutation promotes not only larger oligomers and enhanced cytotoxicity in brain slices than the wild type but also a narrow hydrophobic cavity suitable for fatty acid or phospholipid binding. Here, we determine the plausibility of a novel cytotoxic mechanism where the G6W's structural motif could perturb lipid homeostasis by determining its lipid binding selectivity and specificity. We show that the G6W oligomers have a strong affinity toward unsaturated phospholipids with a preference toward phospholipids containing 16-C alkyl chains. Molecular dynamics simulations demonstrate how an unsaturated, 16-C phospholipid fits tightly inside and outside G6W's hydrophobic cavity. This binding is exclusive to the G6W peptide, as other amyloid oligomers with different atomic structures, including its wildtype αB-Crystallin (90-100) and several superoxide dismutase 1 (SOD1) peptides that are known to self-assemble into amyloid oligomers (SOD1P28K and SOD1WG-GW), do not experience the same strong binding affinity. While the existing chaperone-lipid hypothesis on amyloid toxicity suggests amyloid-lipid complexes perforate cell membranes, our work provides a new outlook, indicating that soluble amyloid oligomers disrupt lipid homeostasis via selective protein-ligand interactions. The toxic mechanisms may arise from the formation of unique amyloid oligomer structures assisted by lipid ligands or impaired lipid transports.

Keywords:  amyloid oligomers; ion-mobility mass spectrometry; lipid ligand binding; molecular dynamics; neurodegenerative diseases; transmission electron microscopy

DOI:  https://doi.org/10.1021/acschemneuro.3c00830
J Cereb Blood Flow Metab. 2024 Mar 14. 271678X241239783

Metabolic coupling between glutamate and N-acetylaspartate in the human brain.

Sungtak Hong, Jyoti Singh Tomar, Jun Shen.

  A metabolic coupling between glutamate and N-acetylaspartate measured by in vivo magnetic resonance spectroscopy has been recently reported in the literature with inconsistent findings. In this study, confounders originating from Pearson's spurious correlation of ratios and spectral correlation due to overlapping magnetic resonance spectroscopy signals of glutamate and N-acetylaspartate were practically eliminated to facilitate the determination of any metabolic link between glutamate and N-acetylaspartate in the human brain using in vivo magnetic resonance spectroscopy. In both occipital and medial prefrontal cortices of healthy individuals, correlations between glutamate and N-acetylaspartate were found to be insignificant. Our results do not lend support to a recent hypothesis that N-acetylaspartate serves as a significant reservoir for the rapid replenishment of glutamate during signaling or stress.

Keywords:  Magnetic resonance spectroscopy; Monte Carlo analysis; Pearson’s spurious correlation of ratios; glutamate metabolism; spectral correlation

DOI:  https://doi.org/10.1177/0271678X241239783
Curr Pharm Des. 2024 Mar 12.

Revisiting the Mitochondrial Function and Communication in Neurodegenerative Diseases.

Nitu L Wankhede, Mayur B Kale, Mohit D Umare, Sanket Lokhande, Aman B Upaganlawar, Pranay Wal, Brijesh G Taksande, Milind J Umekar, Prasanna Shama Khandige, Bhupendra Singh, Vandana Sadananda, Seema Ramniwas, Tapan Behl.

  Neurodegenerative disorders are distinguished by the progressive loss of anatomically or physiologically relevant neural systems. Atypical mitochondrial morphology and metabolic malfunction are found in many neurodegenerative disorders. Alteration in mitochondrial function can occur as a result of aberrant mitochondrial DNA, altered nuclear enzymes that interact with mitochondria actively or passively, or due to unexplained reasons. Mitochondria are intimately linked to the Endoplasmic reticulum (ER), and ER-mitochondrial communication governs several of the physiological functions and procedures that are disrupted in neurodegenerative disorders. Numerous researchers have associated these disorders with ER-mitochondrial interaction disturbance. In addition, aberrant mitochondrial DNA mutation and increased ROS production resulting in ionic imbalance and leading to functional and structural alterations in the brain as well as cellular damage may have an essential role in disease progression via mitochondrial malfunction. In this review, we explored the evidence highlighting the role of mitochondrial alterations in neurodegenerative pathways in most serious ailments, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

Keywords:  Alzheimer’s disease; Huntington’s disease; Neurodegenerative disorders; Parkinson’s disease; endoplasmic reticulum.; mitochondrial communication

DOI:  https://doi.org/10.2174/0113816128286655240304070740
Mol Genet Metab Rep. 2024 Mar;38 101053

Long term follow-up in GAMT deficiency - Correlation of therapy regimen, biochemical and in vivo brain proton MR spectroscopy data.

Lara M Marten, Ralph Krätzner, Gajja S Salomons, Matilde Fernandez Ojeda, Peter Dechent, Jutta Gärtner, Peter Huppke, Steffi Dreha-Kulaczewski.

  GAMT deficiency is a rare autosomal recessive disease within the group of cerebral creatine deficiency syndromes. Cerebral creatine depletion and accumulation of guanidinoacetate (GAA) lead to clinical presentation with intellectual disability, seizures, speech disturbances and movement disorders. Treatment consists of daily creatine supplementation to increase cerebral creatine, reduction of arginine intake and supplementation of ornithine for reduction of toxic GAA levels. This study represents the first long-term follow-up over a period of 14 years, with detailed clinical data, biochemical and multimodal neuroimaging findings. Developmental milestones, brain MRI, quantitative single voxel 1H magnetic resonance spectroscopy (MRS) and biochemical analyses were assessed. The results reveal insights into the dose dependent effects of creatine/ornithine supplementation and expand the phenotypic spectrum of GAMT deficiency. Of note, the creatine concentrations, which were regularly monitored over a long follow-up period, increased significantly over time, but did not reach age matched control ranges. Our patient is the second reported to show normal neurocognitive outcome after an initial delay, stressing the importance of early diagnosis and treatment initiation.

Keywords:  Creatine-supplementation; GAMT-deficiency; MR-spectroscopy; Neurodevelopmental disorder; Neurometabolism

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101053
Front Cell Dev Biol. 2024 ;12 1357862

Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex.

Francisca Cornejo, Nayhara Franchini, Bastián I Cortés, Daniela Elgueta, Gonzalo I Cancino.

  Neurodevelopmental disorders are characterized by alterations in the development of the cerebral cortex, including aberrant changes in the number and function of neural cells. Although neurogenesis is one of the most studied cellular processes in these pathologies, little evidence is known about glial development. Genetic association studies have identified several genes associated with neurodevelopmental disorders. Indeed, variations in the PTPRD gene have been associated with numerous brain disorders, including autism spectrum disorder, restless leg syndrome, and schizophrenia. We previously demonstrated that constitutive loss of PTPRD expression induces significant alterations in cortical neurogenesis, promoting an increase in intermediate progenitors and neurons in mice. However, its role in gliogenesis has not been evaluated. To assess this, we developed a conditional knockout mouse model lacking PTPRD expression in telencephalon cells. Here, we found that the lack of PTPRD in the mouse cortex reduces glial precursors, astrocytes, and oligodendrocytes. According to our results, this decrease in gliogenesis resulted from a reduced number of radial glia cells at gliogenesis onset and a lower gliogenic potential in cortical neural precursors due to less activation of the JAK/STAT pathway and reduced expression of gliogenic genes. Our study shows PTPRD as a regulator of the glial/neuronal balance during cortical neurodevelopment and highlights the importance of studying glial development to understand the etiology of neurodevelopmental diseases.

Keywords:  PTPRD; astrocytes; brain cortex; glia; gliogenesis; neural precursor cells; neurodevelopment; oligodendrocytes

DOI:  https://doi.org/10.3389/fcell.2024.1357862
Res Sq. 2024 Feb 21. pii: rs.3.rs-3970470. [Epub ahead of print]

Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson's Disease and Parkinsonism-Dementia of Guam.

Muralidhar Hegde, Velmarini Vasquez, Manohar Kodavati, Joy Mitra, Indira Vendula, Dale Hamilton, Ralph Garruto, K S Rao.

Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscore the role of α-Syn's mitochondrial localization in inducing TOM40 degradation. Parkinson's Disease related etiological factors, such as 6-hydroxy dopamine or ROS/metal ions stress, which promote α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.

DOI: https://doi.org/10.21203/rs.3.rs-3970470/v1
Biochemistry (Mosc). 2023 Dec;88(12): 1972-1986

Changes in the Glutamate/GABA System in the Hippocampus of Rats with Age and during Alzheimer's Disease Signs Development.

Alena O Burnyasheva, Natalia A Stefanova, Nataliya G Kolosova, Darya V Telegina.

  GABA and glutamate are the most abundant neurotransmitters in the CNS and play a pivotal part in synaptic stability/plasticity. Glutamate and GABA homeostasis is important for healthy aging and reducing the risk of various neurological diseases, while long-term imbalance can contribute to the development of neurodegenerative disorders, including Alzheimer's disease (AD). Normalization of the homeostasis has been discussed as a promising strategy for prevention and/or treatment of AD, however, data on the changes in the GABAergic and glutamatergic systems with age, as well as on the dynamics of AD development, are limited. It is not clear whether imbalance of the excitatory/inhibitory systems is the cause or the consequence of the disease development. Here we analyzed the age-related alterations of the levels of glutamate, GABA, as well as enzymes that synthesize them (glutaminase, glutamine synthetase, GABA-T, and GAD67), transporters (GLAST, GLT-1, and GAT1), and relevant receptors (GluA1, NMDAR1, NMDA2B, and GABAAr1) in the whole hippocampus of the Wistar rats and of the senescence-accelerated OXYS rats, a model of the most common (> 95%) sporadic AD. Our results suggest that there is a decline in glutamate and GABA signaling with age in hippocampus of the both rat strains. However, we have not identified significant changes or compensatory enhancements in this system in the hippocampus of OXYS rats during the development of neurodegenerative processes that are characteristic of AD.

Keywords:  Alzheimer’s disease; GABA; OXYS rats; aging; glutamate; hippocampus

DOI:  https://doi.org/10.1134/S0006297923120027
Mol Neurodegener. 2024 Mar 11. 19(1): 24

APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12.

Jordy Sepulveda, Jennifer Yejean Kim, Joseph Binder, Stefano Vicini, G William Rebeck.

  Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer's disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter. To study microglia surveillance, we imaged microglia baseline motility for 20 min and measured the extension and retraction of processes. We found that APOE4 microglia exhibited significantly less brain surveillance (27%) compared to APOE3 microglia in 6-month-old mice; aging exacerbated this deficit. To measure microglia response to damage, we imaged process motility in response to ATP, an injury-associated signal, for 30 min. We found APOE4 microglia extended their processes significantly slower (0.9 µm/min, p < 0.005) than APOE3 microglia (1.1 μm/min) in 6-month-old animals. APOE-associated alterations in microglia motility were observed in 12- and 21-month-old animals, and this effect was exacerbated with aging in APOE4 microglia. We measured protein and mRNA levels of P2RY12, a core microglial receptor required for process movement in response to damage. We found that APOE4 microglia express significantly less P2RY12 receptors compared to APOE3 microglia despite no changes in P2RY12 transcripts. To examine if the effect of APOE4 on the microglial response to ATP also applied to amyloid β (Aβ), we infused locally Hi-Lyte Fluor 555-labeled Aβ in acute brain slices of 6-month-old mice and imaged microglia movement for 2 h. APOE4 microglia showed a significantly slower (p < 0.0001) process movement toward the Aβ, and less Aβ coverage at early time points after Aβ injection. To test whether P2RY12 is involved in process movement in response to Aβ, we treated acute brain slices with a P2RY12 antagonist before Aβ injection; microglial processes no longer migrated towards Aβ. These results provide mechanistic insights into the impact of APOE4 genotype and aging in dynamic microglial behaviors prior to gross Aβ pathology and could help explain how APOE4 brains are more susceptible to AD pathogenesis.

Keywords:   Ex-vivo imaging; APOE4; Aging; Alzheimer’s disease; Microglia; P2RY12

DOI:  https://doi.org/10.1186/s13024-024-00714-y
EJNMMI Res. 2024 Mar 12. 14(1): 28

Evidence of brain metabolism redistribution from neocortex to primitive brain structures in early acute COVID-19 respiratory syndrome.

Stephan P M Souza, Nicoli Colet, Mariana Fujiwara, Alins P Fernandes, Natalia Tobar, Sergio S J Dertkigil, Maria Emilia S Takahashi, Bárbara J Amorim, Lucas S Silva, Clarissa L Yasuda, Fernando Cendes, Thiago F de Souza, Juliano T Rodrigues, Denise E Zantut-Wittmann, Celso Dario Ramos.

   BACKGROUND: Neuropsychiatric sequelae of COVID-19 have been widely documented in patients with severe neurological symptoms during the chronic or subacute phase of the disease. However, it remains unclear whether subclinical changes in brain metabolism can occur early in the acute phase of the disease. The aim of this study was to identify and quantify changes in brain metabolism in patients hospitalized for acute respiratory syndrome due to COVID-19 with no or mild neurological symptoms.
RESULTS: Twenty-three non-intubated patients (13 women; mean age 55.5 ± 12.1 years) hospitalized with positive nasopharyngeal swab test (RT-PCR) for COVID-19, requiring supplemental oxygen and no or mild neurological symptoms were studied. Serum C-reactive protein measured at admission ranged from 6.43 to 189.0 mg/L (mean: 96.9 ± 54.2 mg/L). The mean supplemental oxygen demand was 2.9 ± 1.4 L/min. [18F]FDG PET/CT images were acquired with a median of 12 (4-20) days of symptoms. After visual interpretation of the images, semiquantitative analysis of [18F]FDG uptake in multiple brain regions was evaluated using dedicated software and the standard deviation (SD) of brain uptake in each region was automatically calculated in comparison with reference values of a normal database. Evolutionarily ancient structures showed positive SD mean values of [18F]FDG uptake. Lenticular nuclei were bilaterally hypermetabolic (> 2 SD) in 21/23 (91.3%) patients, and thalamus in 16/23 (69.6%), bilaterally in 11/23 (47.8%). About half of patients showed hypermetabolism in brainstems, 40% in hippocampi, and 30% in cerebellums. In contrast, neocortical regions (frontal, parietal, temporal and occipital lobes) presented negative SD mean values of [18F]FDG uptake and hypometabolism (< 2 SD) was observed in up to a third of patients. Associations were found between hypoxia, inflammation, coagulation markers, and [18F]FDG uptake in various brain structures.
CONCLUSIONS: Brain metabolism is clearly affected during the acute phase of COVID-19 respiratory syndrome in neurologically asymptomatic or oligosymptomatic patients. The most frequent finding is marked hypermetabolism in evolutionary ancient structures such as lenticular nucleus and thalami. Neocortical metabolism was reduced in up to one third of patients, suggesting a redistribution of brain metabolism from the neocortex to evolutionary ancient brain structures in these patients.

Keywords:  Brain metabolism; COVID-19; FDG; Metabolism redistribution; Positron emission tomography/computed tomography; Quantification

DOI:  https://doi.org/10.1186/s13550-024-01089-3
bioRxiv. 2024 Feb 28. pii: 2023.08.18.553810. [Epub ahead of print]

13 C-SpaceM: Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.

Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Shahraz Mohammed, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.

Metabolism has emerged as a key factor in homeostasis and disease including cancer. Yet, little is known about the heterogeneity of metabolic activity of cancer cells due to the lack of tools to directly probe it. Here, we present a novel method, 13 C-SpaceM for spatial single-cell isotope tracing of glucose-dependent de novo lipogenesis. The method combines imaging mass spectrometry for spatially-resolved detection of 13 C 6 -glucose-derived 13 C label incorporated into esterified fatty acids with microscopy and computational methods for data integration and analysis. We validated 13 C-SpaceM on a spatially-heterogeneous normoxia-hypoxia model of liver cancer cells. Investigating cultured cells, we revealed single-cell heterogeneity of lipogenic acetyl-CoA pool labelling degree upon ACLY knockdown that is hidden in the bulk analysis and its effect on synthesis of individual fatty acids. Next, we adapted 13 C-SpaceM to analyze tissue sections of mice harboring isocitrate dehydrogenase (IDH)-mutant gliomas. We found a strong induction of de novo fatty acid synthesis in the tumor tissue compared to the surrounding brain. Comparison of fatty acid isotopologue patterns revealed elevated uptake of mono-unsaturated and essential fatty acids in the tumor. Furthermore, our analysis uncovered substantial spatial heterogeneity in the labelling of the lipogenic acetyl-CoA pool indicative of metabolic reprogramming during microenvironmental adaptation. Overall, 13 C-SpaceM enables novel ways for spatial probing of metabolic activity at the single cell level. Additionally, this methodology provides unprecedented insight into fatty acid uptake, synthesis and modification in normal and cancerous tissues.

DOI: https://doi.org/10.1101/2023.08.18.553810
Biopharm Drug Dispos. 2024 Mar 15.

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs.

K Sandy Pang, H Benson Peng, Betty P Li, Binyu Wen, Keumhan Noh, Runyu Xia, Anja Toscan, Sylvia Serson, Paul E Fraser, Rommel G Tirona, Inès A M de Lannoy.

  Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42 ) peptides, Mdr1 and APP (amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40 weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40 , and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20 weeks old toward 40 weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

Keywords:  Abca1; Cyp46a1; aging; amyloid-β peptides; free cholesterol; guinea pig

DOI:  https://doi.org/10.1002/bdd.2386
Res Sq. 2024 Feb 27. pii: rs.3.rs-3973736. [Epub ahead of print]

Integrative brain omics approach reveals key role for sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.

Eric Ortlund, Chih-Yu Chen, Kristal Maner-Smith, Manoj Khadka, Jun Ahn, Xueyun Gulbin, Anna Ivanova, Eric Dammer, Nicholas Seyfried, David Bennett, Ihab Hajjar.

The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. We utilized non-targeted mass spectrometry to examine brain lipids variations across 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as either control, asymptomatic AD (AAD), or symptomatic AD (SAD) and integrated the lipidomics data with untargeted proteomic characterization on the same individuals. Lipid enrichment analysis and analysis of variance identified significantly lower abundance of lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species in SAD than controls or AAD. Lipid-protein co-expression network analyses revealed that lipid modules consisting of LPE and LPC exhibited a significant association to protein modules associated with MAPK/metabolism, post-synaptic density, and Cell-ECM interaction pathways and were associated with better antemortem cognition and with neuropathological changes seen in AD. Particularly, LPE 22:6 [sn-1] levels are significantly decreased across AD cases (SAD) and show the most influence on protein changes compared to other lysophospholipid species. LPE 22:6 may be a lipid signature for AD and could be leveraged as potential therapeutic or dietary targets for AD.

DOI: https://doi.org/10.21203/rs.3.rs-3973736/v1
Nature. 2024 Mar 13.

Mitochondrial complex I activity in microglia sustains neuroinflammation.

L Peruzzotti-Jametti, C M Willis, G Krzak, R Hamel, L Pirvan, R-B Ionescu, J A Reisz, H A Prag, M E Garcia-Segura, V Wu, Y Xiang, B Barlas, A M Casey, A M R van den Bosch, A M Nicaise, L Roth, G R Bates, H Huang, P Prasad, A E Vincent, C Frezza, C Viscomi, G Balmus, Z Takats, J C Marioni, A D'Alessandro, M P Murphy, I Mohorianu, S Pluchino.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.

DOI: https://doi.org/10.1038/s41586-024-07167-9
J Biol Chem. 2024 Mar 11. pii: S0021-9258(24)01654-5. [Epub ahead of print] 107159

Fatty acid oxidation drives mitochondrial hydrogen peroxide production by α-ketoglutarate dehydrogenase.

Cathryn Grayson, Ben Faerman, Olivia Koufos, Ryan J Mailloux.

In the present study, we examined the mitochondrial hydrogen peroxide (mH2O2) generating capacity of α-ketoglutarate dehydrogenase (KGDH) and compared it to components of the electron transport chain (ETC) using liver mitochondria isolated from male and female C57BL6N mice. We show for the first time there are some sex dimorphisms in the production of mH2O2 by ETC complexes I and III when mitochondria are fueled with different substrates. However, in our investigations into these sex effects, we made the unexpected discovery that: 1. KGDH serves as a major mH2O2 supplier in male and female liver mitochondria and 2. KGDH can form mH2O2 when mitochondria are energized with fatty acids, but only when malate is used to prime the Krebs cycle. Surprisingly, 2-keto-3-methylvaleric acid (KMV), a site-specific inhibitor for KGDH, nearly abolished mH2O2 generation in both male and female liver mitochondria oxidizing palmitoyl-carnitine. KMV inhibited mH2O2 production in liver mitochondria from male and female mice oxidizing myristoyl-, octanoyl-, or butyryl-carnitine. S1QEL 1.1 (S1) and S3QEL 2 (S3), compounds that inhibit reactive oxygen species (ROS) generation by complexes I and III, respectively, without interfering with OxPhos, had a negligible effect on the rate of mH2O2 production when pyruvate or acyl-carnitines were used as fuels. However, inclusion of KMV in reaction mixtures containing S1 and/or S3 almost abolished mH2O2 generation. Together, our findings suggest KGDH is the main mH2O2 generator in liver mitochondria, even when fatty acids are used as fuel.

DOI: https://doi.org/10.1016/j.jbc.2024.107159
Nature. 2024 Mar 13.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Michael S Haney, Róbert Pálovics, Christy Nicole Munson, Chris Long, Patrik K Johansson, Oscar Yip, Wentao Dong, Eshaan Rawat, Elizabeth West, Johannes C M Schlachetzki, Andy Tsai, Ian Hunter Guldner, Bhawika S Lamichhane, Amanda Smith, Nicholas Schaum, Kruti Calcuttawala, Andrew Shin, Yung-Hua Wang, Chengzhong Wang, Nicole Koutsodendris, Geidy E Serrano, Thomas G Beach, Eric M Reiman, Christopher K Glass, Monther Abu-Remaileh, Annika Enejder, Yadong Huang, Tony Wyss-Coray.

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

DOI: https://doi.org/10.1038/s41586-024-07185-7
Elife. 2024 Mar 14. pii: e92376. [Epub ahead of print]13

Activity-dependent mitochondrial ROS signaling regulates recruitment of glutamate receptors to synapses.

Rachel L Doser, Kaz M Knight, Ennis W Deihl, Frederic J Hoerndli.

  Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the transparent genetic model Caenorhabditis elegans, we were able to manipulate and measure mitochondrial ROS (reactive oxygen species) signaling of individual mitochondria as well as neuronal activity of single neurons in vivo. Using this approach, we provide evidence supporting a novel role for mitochondrial ROS signaling in dendrites of excitatory glutamatergic C. elegans interneurons. Specifically, we show that following neuronal activity, dendritic mitochondria take up calcium (Ca2+) via the mitochondrial Ca2+ uniporter MCU-1 that results in an upregulation of mitochondrial ROS production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the C. elegans ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is upregulated when MCU-1 function is pharmacologically or genetically impaired but is downregulated by mitoROS signaling. Thus, signaling from postsynaptic mitochondria may regulate excitatory synapse function to maintain neuronal homeostasis by preventing excitotoxicity and energy depletion.

Keywords:  C. elegans; cell biology; neuroscience

DOI:  https://doi.org/10.7554/eLife.92376