bims-medebr 2024-10-20 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–10–20
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

Fatty acid β-oxidation in brain mitochondria: Insights from high-resolution respirometry in mouse, rat and Drosophila brain, ischemia and aging models.
Role and Function of Peroxisomes in Neuroinflammation.
Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.
PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.
Phospholipids, Sphingolipids, and Cholesterol-Derived Lipid Mediators and Their Role in Neurological Disorders.
Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.
Molecular determinants of phospholipid treatment to reduce intracellular cholesterol accumulation in NPC1 deficiency.
Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.
APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.
TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis.
The ketone body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants.
Ceramide lowering rescues respiratory defects in a Drosophila model of acid sphingomyelinase deficiency.
Investigation of Lysophospholipids-DHA transport across an in vitro human model of blood brain barrier.
Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis.
APOE 𝜀4-related blood-brain barrier breakdown is associated with microstructural abnormalities.
A single dose of glycogen phosphorylase inhibitor improves cognitive functions of aged mice and affects the concentrations of metabolites in the brain.
Apolipoprotein B gene expression and regulation in relation to Alzheimer's disease pathophysiology.
Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model.
Associations between elevated uric acid and brain imaging abnormalities in pediatric patients with methylmalonic acidemia under 5 years of age.

Biochim Biophys Acta Mol Basis Dis. 2024 Oct 16. pii: S0925-4439(24)00538-6. [Epub ahead of print] 167544

Fatty acid β-oxidation in brain mitochondria: Insights from high-resolution respirometry in mouse, rat and Drosophila brain, ischemia and aging models.

Luiza H D Cardoso, Cristiane Cecatto, Melita Ozola, Stanislava Korzh, Liga Zvejniece, Baiba Gukalova, Carolina Doerrier, Maija Dambrova, Marina Makrecka-Kuka, Erich Gnaiger, Edgars Liepinsh.

  Glucose is the main energy source of the brain, yet recent studies demonstrate that fatty acid oxidation (FAO) plays a relevant role in the pathogenesis of central nervous system disorders. We evaluated FAO in brain mitochondria under physiological conditions, in the aging brain, and after stroke. Using high-resolution respirometry we compared medium-chain (MC, octanoylcarnitine) and long-chain (LC, palmitoylcarnitine) acylcarnitines as substrates of β-oxidation in the brain. The protocols developed avoid FAO overestimation by malate-linked anaplerotic activity in brain mitochondria. The capacity of FA oxidative phosphorylation (F-OXPHOS) with palmitoylcarnitine was up to 4 times higher than respiration with octanoylcarnitine. The optimal concentration of palmitoylcarnitine was 10 μM which corresponds to the total concentration of LC acylcarnitines in the brain. Maximal respiration with octanoylcarnitine was reached at 20 μM, however, this concentration exceeds MC acylcarnitine concentrations in the brain 15 times. F-OXPHOS capacity was highest in mouse cerebellum, intermediate in cortex, prefrontal cortex, and hypothalamus, and hardly detectable in hippocampus. F-OXPHOS capacity was 2-fold lower and concentrations of LC acylcarnitines were 2-fold higher in brain of aged rats. A similar trend was observed in the rat model of endothelin-1-induced stroke, but reduction of OXPHOS capacity was not limited to FAO. In conclusion, although FAO is not a dominant pathway in brain bioenergetics, it deserves specific attention in studies of brain metabolism.

Keywords:  Acylcarnitines; Beta-oxidation; Brain; Fatty acid oxidation; Mitochondrial function; Nervous system; Respirometry

DOI:  https://doi.org/10.1016/j.bbadis.2024.167544
Cells. 2024 Oct 05. pii: 1655. [Epub ahead of print]13(19):

Role and Function of Peroxisomes in Neuroinflammation.

Chinmoy Sarkar, Marta M Lipinski.

  Peroxisomes are organelles involved in many cellular metabolic functions, including the degradation of very-long-chain fatty acids (VLCFAs; C ≥ 22), the initiation of ether-phospholipid synthesis, and the metabolism of reactive oxygen species. All of these processes are essential for the maintenance of cellular lipid and redox homeostasis, and their perturbation can trigger inflammatory response in immune cells, including in the central nervous system (CNS) resident microglia and astrocytes. Consistently, peroxisomal disorders, a group of congenital diseases caused by a block in peroxisomal biogenesis or the impairment of one of the peroxisomal enzymes, are associated with neuroinflammation. Peroxisomal function is also dysregulated in many neurodegenerative diseases and during brain aging, both of which are associated with neuroinflammation. This suggests that deciphering the role of peroxisomes in neuroinflammation may be important for understanding both congenital and age-related brain dysfunction. In this review, we discuss the current advances in understanding the role and function of peroxisomes in neuroinflammation.

Keywords:  ether phospholipids; neuroinflammation; peroxisomal disorders; peroxisomes; very-long-chain fatty acids

DOI:  https://doi.org/10.3390/cells13191655
Sci Adv. 2024 Oct 18. 10(42): eadp1115

Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.

Carlos G Ardanaz, Aida de la Cruz, Paras S Minhas, Nira Hernández-Martín, Miguel Ángel Pozo, M Pilar Valdecantos, Ángela M Valverde, Palmira Villa-Valverde, Marcos Elizalde-Horcada, Elena Puerta, María J Ramírez, Jorge E Ortega, Ainhoa Urbiola, Cristina Ederra, Mikel Ariz, Carlos Ortiz-de-Solórzano, Joaquín Fernández-Irigoyen, Enrique Santamaría, Gerard Karsenty, Jens C Brüning, Maite Solas.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e., GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 reduction (GLUT1ΔGFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Mechanistically, we observed that GLUT1-deficient astrocytes exhibited increased insulin receptor-dependent ATP release, and that both astrocyte insulin signaling and brain purinergic signaling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its depletion triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis, and cognitive function.

DOI: https://doi.org/10.1126/sciadv.adp1115
Cell. 2024 Oct 15. pii: S0092-8674(24)01094-8. [Epub ahead of print]

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

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

  Bis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, particularly 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 risk of Alzheimer's disease, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomal S,S-BMP, a crucial lipid for maintaining brain health.

Keywords:  Alzheimer’s disease; dementia; gangliosides; lipid metabolism; lysosome; neurodegeneration; phospholipid

DOI:  https://doi.org/10.1016/j.cell.2024.09.036
Int J Mol Sci. 2024 Oct 03. pii: 10672. [Epub ahead of print]25(19):

Phospholipids, Sphingolipids, and Cholesterol-Derived Lipid Mediators and Their Role in Neurological Disorders.

Akhlaq A Farooqui, Tahira Farooqui.

  Neural membranes are composed of phospholipids, sphingolipids, cholesterol, and proteins. In response to cell stimulation or injury, the metabolism of lipids generates various lipid mediators, which perform many cellular functions. Thus, phospholipids release arachidonic acid or docosahexaenoic acid from the sn-2 position of the glycerol moiety by the action of phospholipases A2. Arachidonic acid is a precursor for prostaglandins, leukotrienes, thromboxane, and lipoxins. Among these mediators, prostaglandins, leukotrienes, and thromboxane produce neuroinflammation. In contrast, lipoxins produce anti-inflammatory and pro-resolving effects. Prostaglandins, leukotrienes, and thromboxane are also involved in cell proliferation, differentiation, blood clotting, and blood vessel permeability. In contrast, DHA-derived lipid mediators are called specialized pro-resolving lipid metabolites (SPMs). They include resolvins, protectins, and maresins. These mediators regulate immune function by producing anti-inflammatory, pro-resolving, and cell protective effects. Sphingolipid-derived metabolites are ceramide, ceramide1-phosphate, sphingosine, and sphingosine 1 phosphate. They regulate many cellular processes, including enzyme activities, cell migration and adhesion, inflammation, and immunity. Cholesterol is metabolized into hydroxycholesterols and 7-ketocholesterol, which not only disrupts membrane fluidity, but also promotes inflammation, oxidative stress, and apoptosis. These processes lead to cellular damage.

Keywords:  4-hydroxyhexanal; 4-hydroxynonal; 7-ketocholesterol; arachidonic acid; ceramide-1-phosphate; docosahexaenoic acid; hydroxycholesterol; isoprostane; leukotrienes; lipoxins; maresins; neuroprostane; phospholipids; prostaglandins; protectins; resolvins; sphingosine; sphingosine 1-phosphate; thromboxane

DOI:  https://doi.org/10.3390/ijms251910672
Mol Genet Metab. 2024 Oct 12. pii: S1096-7192(24)00479-7. [Epub ahead of print]143(3): 108595

Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8.

Nicola Longo, Laura Alane Voss, Marta Frigeni, Bijina Balakrishnan, Marzia Pasquali.

  Cerebral creatine deficiency syndromes (CCDS) are rare inherited metabolic disorders caused by defective biosynthesis or transport of creatine. These conditions are characterized by reduced accumulation of creatine in the brain, mild to severe intellectual disability, global developmental delay, and speech-language disorders. The amount of brain creatine reduction needed to cause symptoms is not known. Here we report a new patient with creatine transporter deficiency (CTD) who presented at 15 months of age with seizures and global delays with no speech at 3 years of age. Brain MRI was normal, but brain MRS indicated creatine levels reduced to about 20 % of normal. He had normal levels of creatine and guanidinoacetate in plasma, but increased creatine/creatinine ratio in urine. DNA sequencing identified a hemizygous c.832C > T (p.Arg278Cys) variant in the creatine transporter gene SLC6A8. Fibroblasts from this patient had about 25 % of normal creatine transport activity, a value much higher than that measured in patients whose variants introduced premature stop codons in SLC6A8. The child was started on supplements of creatine, glycine, and arginine. His speech improved dramatically, and he had no more seizures, even during episodes of fever. Despite the clinical improvement, a repeat MRS demonstrated similar levels of brain creatine. This study suggests that a reduction in creatine transporter activity to 25 % or less is sufficient to cause symptoms of brain creatine deficiency and that functionally milder forms of CTD might respond to supplements aimed at replenishing brain creatine.

Keywords:  Creatine transport; Creatine transporter deficiency; Magnetic resonance spectroscopy

DOI:  https://doi.org/10.1016/j.ymgme.2024.108595
J Biol Chem. 2024 Oct 10. pii: S0021-9258(24)02391-3. [Epub ahead of print] 107889

Molecular determinants of phospholipid treatment to reduce intracellular cholesterol accumulation in NPC1 deficiency.

Shikun Deng, Ting-Ann Liu, Olga Ilnytska, Tamara Allada, Angelina Fomina, Nancy Lin, Valentina Z Petukhova, Kolege C Pathmasiri, Kiran Chinthapally, Brian S J Blagg, Brandon L Ashfeld, Stephanie M Cologna, Judith Storch.

  Niemann-Pick type C (NPC) disease, caused by mutations in the NPC1 or NPC2 genes, leads to abnormal intracellular cholesterol accumulation in late endosomes/lysosomes (LE/LY). Exogenous enrichment with lysobisphosphatidic acid (LBPA), also known as bis-monoacylglycerol phosphate or BMP, either directly or via the LBPA precursor phosphatidylglycerol (PG), has been investigated as a therapeutic intervention to reduce cholesterol accumulation in NPC disease. Here we report the effects of stereoisomer configuration and acyl chain composition of LBPA on cholesterol clearance in NPC1-deficient cells. We find that S,R, S,S, and S,R LBPA stereoisomers behaved similarly, with all 3 compounds leading to comparable reductions in filipin staining in two NPC1-deficient human fibroblast cell lines. Examination of several LBPA molecular species containing one or two mono- or polyunsaturated acyl chains showed that all LBPA species containing one 18:1 chain significantly reduced cholesterol accumulation, whereas the shorter chain species di-14:0 LBPA had little effect on cholesterol clearance in NPC1 deficient cells. Since cholesterol accumulation in NPC1 deficient cells can also be cleared by PG incubation, we used non-hydrolyzable PG analogues to determine whether conversion to LBPA is required for sterol clearance, or whether PG itself is effective. The results showed that non-hydrolyzable PG species were not appreciably converted to LBPA and showed virtually no cholesterol clearance efficacy in NPC1 deficient cells, supporting the notion that LBPA is the active agent promoting LE/LY cholesterol clearance. Overall these studies are helping to define the molecular requirements for potential therapeutic use of LBPA as an option for addressing NPC disease.

Keywords:  Niemann-Pick C Disease; bis-monoacylglycerol phosphate; cholesterol; lysobis-phosphatidic acid; lysosome; phosphatidylglycerol; phospholipid

DOI:  https://doi.org/10.1016/j.jbc.2024.107889
Biochim Biophys Acta Proteins Proteom. 2024 Oct 10. pii: S1570-9639(24)00062-1. [Epub ahead of print] 141055

Ndufs4 knockout mice with isolated complex I deficiency engage a futile adaptive brain response.

Melissa A E van de Wal, Cenna Doornbos, Janne Bibbe, Judith R Homberg, Clara van Karnebeek, Martijn A Huynen, Jaap Keijer, Evert M van Schothorst, Peter A C 't Hoen, Mirian C H Janssen, Merel J W Adjobo-Hermans, Mariusz R Wieckowski, Werner J H Koopman.

  Paediatric Leigh syndrome (LS) is an early-onset and fatal neurodegenerative disorder lacking treatment options. LS is frequently caused by mutations in the NDUFS4 gene, encoding an accessory subunit of mitochondrial complex I (CI), the first complex of the oxidative phosphorylation (OXPHOS) system. Whole-body Ndufs4 knockout (KO) mice (WB-KO mice) are widely used to study isolated CI deficiency, LS pathology and interventions. These animals develop a brain-specific phenotype via an incompletely understood pathomechanism. Here we performed a quantitative analysis of the sub-brain proteome in six-weeks old WB-KO mice vs. wildtype mice. Brain regions comprised of a brain slice (BrSl), cerebellum (CB), cerebral cortex (CC), hippocampus (HC), inferior colliculus (IC), and superior colliculus (SC). Proteome analysis demonstrated similarities between CC/HC, and between IC/SC, whereas BrSl and CB differed from these two groups and each other. All brain regions displayed greatly reduced levels of two CI structural subunits (NDUFS4, NDUFA12) and an increased level of the CI assembly factor NDUFAF2. The level of CI-Q module subunits was significantly more reduced in IC/SC than in BrSl/CB/CC/HC, whereas other OXPHOS complex levels were not reduced. Gene ontology and pathway analysis demonstrated specific and common proteome changes between brain regions. Across brain regions, upregulation of cold-shock-associated proteins, mitochondrial fatty acid (FA) oxidation and synthesis (mtFAS) were the most prominent. FA-related pathways were predominantly upregulated in CB and HC. Based upon these results, we argue that stimulation of these pathways is futile and pro-pathological and discuss alternative strategies for therapeutic intervention in LS. SIGNIFICANCE: The Ndufs4 knockout mouse model is currently the most relevant and most widely used animal model to study the brain-linked pathophysiology of human Leigh Syndrome (LS) and intervention strategies. We demonstrate that the Ndufs4 knockout brain engages futile and pro-pathological responses. These responses explain both negative and positive outcomes of intervention studies in Leigh Syndrome mice and patients, thereby guiding novel intervention opportunities.

Keywords:  Brain; Fatty acids; Leigh syndrome; Pathomechanism; Proteomics

DOI:  https://doi.org/10.1016/j.bbapap.2024.141055
bioRxiv. 2024 Oct 07. pii: 2024.10.07.617044. [Epub ahead of print]

APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids.

Karina K Meyer-Acosta, Eva Diaz-Guerra, Parul Varma, Adyasha Aruk, Sara Mirsadeghi, Aranis Muniz Perez, Yousef Rafati, Ali Hosseini, Vanesa Nieto-Estevez, Michele Giugliano, Christopher Navara, Jenny Hsieh.

Apolipoprotein E4 ( APOE4 ) is the leading genetic risk factor for Alzheimer's disease. While most studies examine the role of APOE4 in aging, imaging, and cognitive assessments reveal that APOE4 influences brain structure and function as early as infancy. Here, we examined human-relevant cellular phenotypes across neurodevelopment using induced pluripotent stem cell (iPSC) derived cortical and ganglionic eminence organoids (COs and GEOs). In COs, we showed that APOE4 decreased BRN2+ and SATB2+ cortical neurons, increased astrocytes and outer radial glia, and was associated with increased cell death and dysregulated GABA-related gene expression. In GEOs, APOE4 accelerated maturation of neural progenitors and neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupted network formation and altered response to GABA, resulting in heightened excitability and synchronicity. Together, our data provides new insights into how APOE4 may influence cortical neurodevelopmental processes and network formation in the human brain.

DOI: https://doi.org/10.1101/2024.10.07.617044
bioRxiv. 2024 Oct 09. pii: 2024.10.09.617477. [Epub ahead of print]

TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis.

Jinglei Xu, Jingqi Duan, Zhiqiang Cai, Chie Arai, Chao Di, Christopher C Venters, Jian Xu, Maura Jones, Byung-Ran So, Gideon Dreyfuss.

The patho-mechanism of apolipoprotein variant, APOE4, the strongest genetic risk for late-onset Alzheimer's disease (AD) and longevity, remains unclear. APOE's neighboring gene, TOMM40 (mitochondria protein transport channel), is associated with brain trauma outcome and aging-related cognitive decline, however its role in AD APOE4-independently is controversial. We report that TOMM40 is prone to transcription readthrough into APOE that can generate spliced TOMM40-APOE mRNA chimera (termed T9A2) detected in human neurons and other cells and tissues. T9A2 translation tethers APOE (normal APOE3 or APOE4) to near-full-length TOM40 that is targeted to mitochondria. Importantly, T9A2-APOE3 boosts mitochondrial bioenergetic capacity and decreases oxidative stress significantly more than T9A2-APOE4 and APOE3, and lacking in APOE4. We describe detailed interactomes of these actors that may inform about the activities and roles in pathogenesis. T9A2 uncovers a new candidate pathway for mitochondria regulation and oxidative stress-protection that are impaired in APOE4 genotypes and could initiate neurodegeneration.

DOI: https://doi.org/10.1101/2024.10.09.617477
Elife. 2024 Oct 18. pii: RP94520. [Epub ahead of print]13

The ketone body β-hydroxybutyrate ameliorates neurodevelopmental deficits in the GABAergic system of daf-18/PTEN Caenorhabditis elegans mutants.

Sebastián Giunti, María Gabriela Blanco, María José De Rosa, Diego Rayes.

  A finely tuned balance between excitation and inhibition (E/I) is essential for proper brain function. Disruptions in the GABAergic system, which alter this equilibrium, are a common feature in various types of neurological disorders, including autism spectrum disorders (ASDs). Mutations in Phosphatase and Tensin Homolog (PTEN), the main negative regulator of the phosphatidylinositol 3-phosphate kinase/Akt pathway, are strongly associated with ASD. However, it is unclear whether PTEN deficiencies can differentially affect inhibitory and excitatory signaling. Using the Caenorhabditis elegans neuromuscular system, where both excitatory (cholinergic) and inhibitory (GABAergic) inputs regulate muscle activity, we found that daf-18/PTEN mutations impact GABAergic (but not cholinergic) neurodevelopment and function. This selective impact results in a deficiency in inhibitory signaling. The defects observed in the GABAergic system in daf-18/PTEN mutants are due to reduced activity of DAF-16/FOXO during development. Ketogenic diets (KGDs) have proven effective for disorders associated with E/I imbalances. However, the mechanisms underlying their action remain largely elusive. We found that a diet enriched with the ketone body β-hydroxybutyrate during early development induces DAF-16/FOXO activity, therefore improving GABAergic neurodevelopment and function in daf-18/PTEN mutants. Our study provides valuable insights into the link between PTEN mutations and neurodevelopmental defects and delves into the mechanisms underlying the potential therapeutic effects of KGDs.

Keywords:  C. elegans; GABA; developmental biology; excitation/inhibition balance; ketone bodies; neurodevelopment; neuroscience

DOI:  https://doi.org/10.7554/eLife.94520
Hum Mol Genet. 2024 Oct 15. pii: ddae143. [Epub ahead of print]

Ceramide lowering rescues respiratory defects in a Drosophila model of acid sphingomyelinase deficiency.

Alexander J Hull, Magda L Atilano, Jenny Hallqvist, Wendy Heywood, Kerri J Kinghorn.

  Types A and B Niemann-Pick disease (NPD) are inherited multisystem lysosomal storage disorders due to mutations in the SMPD1 gene. Respiratory dysfunction is a key hallmark of NPD, yet the mechanism for this is underexplored. SMPD1 encodes acid sphingomyelinase (ASM), which hydrolyses sphingomyelin to ceramide and phosphocholine. Here, we present a Drosophila model of ASM loss-of-function, lacking the fly orthologue of SMPD1, dASM, modelling several aspects of the respiratory pathology of NPD. dASM is expressed in the late-embryonic fly respiratory network, the trachea, and is secreted into the tracheal lumen. Loss of dASM results in embryonic lethality, and the tracheal lumen fails to fill normally with gas prior to eclosion. We demonstrate that the endocytic clearance of luminal constituents prior to gas-filling is defective in dASM mutants, and is coincident with autophagic, but not lysosomal defects, in late stage embryonic trachea. Finally, we show that although bulk sphingolipids are unchanged, dietary loss of lipids in combination with genetic and pharmacological block of ceramide synthesis rescues the airway gas-filling defects. We highlight myriocin as a potential therapeutic drug for the treatment of the developmental respiratory defects associated with ASM deficiency, and present a new NPD model amenable to genetic and pharmacological screens.

Keywords:   Drosophila ; SMPD1 ; dASM ; Niemann-Pick; lysosomal storage disorder; lysosome; sphingolipid

DOI:  https://doi.org/10.1093/hmg/ddae143
Heliyon. 2024 Oct 15. 10(19): e38871

Investigation of Lysophospholipids-DHA transport across an in vitro human model of blood brain barrier.

Mayssa Hachem, Abdelmoneim H Ali, Ibrahim Yildiz, Christophe Landry, Fabien Gosselet.

  Several studies emphasized on the preventive and therapeutic potential of Docosahexaenoic Acid (DHA, 22:6n-3) supplementation in chronic and age-related disorders including neurodegenerative diseases. Researchers principally studied the cerebral accretion of Lysophosphatidylcholine (LysoPC-DHA), the furthermost vital Lysophospholipid-DHA (LysoPL-DHA) in blood plasma. Nevertheless, the cerebral bioavailability of other LysoPL-DHA forms including Lysophosphatidylethanolamine (LysoPE-DHA), and Lysophosphatidylserine (LysoPS-DHA) were not extensively examined even though their vital biological functions in the brain. Hence, the aim of the present study was to evaluate the toxicity and transport of DHA in comparison to several LysoPL-DHA including LysoPC-DHA, LysoPE-DHA and LysoPS-DHA across a human model of blood-brain barrier (BBB). The human brain-like endothelial cells (hBLECs) monolayer tightness was evaluated by the parallel assessment of the permeability of fluorescent marker Lucifer yellow (LY) and revealed the absence of toxicity of non-esterified DHA and all LysoPL-DHA towards hBLECs. LysoPC-DHA, LysoPE-DHA and LysoPS-DHA displayed a higher recovery in the abluminal medium in comparison to non-esterified DHA at 30, 60 and 120 min post-incubation. Among all, LysoPS-DHA revealed the highest apparent coefficient permeability (Papp) 85.87 ± 4.24 x 10-6 cm s-1 and was significantly different than DHA, LysoPC-DHA and LysoPE-DHA. More interestingly, when studying the time course of Papp of DHA, LysoPC-DHA and LysoPE-DHA, at different post-incubation time, this permeability decreases with time especially for LysoPC-DHA and LysoPE-DHA, not for DHA. Furthermore, LysoPS-DHA exhibited the highest intracellular accumulation (10.39 ± 0.49 %) in hBLECs in comparison to all other tested lipids. Finally, differences in 3D structures and molecular electrostatic potential maps calculation of LysoPL-DHA could explain the dissimilar cerebral uptake of LysoPL-DHA. Altogether, our findings raise the novel hypothesis that LysoPS-DHA may represent a preferred physiological carrier of DHA to the brain.

Keywords:  Blood-brain-barrier; Brain lipids; Docosahexaenoic acid; Fatty acid transport; LC-MS; Lysophospholipids; Molecular modeling; Omega-3 fatty acids; Recovery

DOI:  https://doi.org/10.1016/j.heliyon.2024.e38871
bioRxiv. 2024 Oct 10. pii: 2024.10.10.617517. [Epub ahead of print]

Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis.

Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley J Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, cardiolipin (CL) was downregulated across four mouse models of MASLD. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous MASH with elevated mitochondrial electron leak. Loss of CL interfered with the ability of coenzyme Q (CoQ) to transfer electrons, promoting leak primarily at sites II F and III Q0 . Data from human liver biopsies revealed a highly robust correlation between mitochondrial CL and CoQ, co-downregulated with MASH. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.

DOI: https://doi.org/10.1101/2024.10.10.617517
Alzheimers Dement. 2024 Oct 16.

APOE 𝜀4-related blood-brain barrier breakdown is associated with microstructural abnormalities.

Emilie T Reas, Seraphina K Solders, Amaryllis Tsiknia, Curtis Triebswetter, Qian Shen, Charlotte S Rivera, Murray J Andrews, Austin Alderson-Myers, James B Brewer.

   INTRODUCTION: Blood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear.
METHODS: Older adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE 𝜀4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4.
RESULTS: BBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers.
DISCUSSION: APOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade.
HIGHLIGHTS: Gray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

Keywords:  APOE; Alzheimer's disease; amyloid; blood–brain barrier; diffusion MRI

DOI:  https://doi.org/10.1002/alz.14302
Sci Rep. 2024 10 15. 14(1): 24123

A single dose of glycogen phosphorylase inhibitor improves cognitive functions of aged mice and affects the concentrations of metabolites in the brain.

Natalia Pudełko-Malik, Dominika Drulis-Fajdasz, Łukasz Pruss, Karolina Anna Mielko-Niziałek, Dariusz Rakus, Agnieszka Gizak, Piotr Młynarz.

  Inhibition of glycogen phosphorylase (Pyg) - a regulatory enzyme of glycogen phosphorolysis - influences memory formation in rodents. We have previously shown that 2-week intraperitoneal administration of a Pyg inhibitor BAY U6751 stimulated the "rejuvenation" of the hippocampal proteome and dendritic spines morphology and improved cognitive skills of old mice. Given the tedious nature of daily intraperitoneal drug administration, in this study we investigated whether a single dose of BAY U6751 could induce enduring behavioral effects. Obtained results support the efficacy of such treatment in significantly improving the cognitive performance of 20-22-month-old mice. Metabolomic analysis of alterations observed in the hippocampus, cerebellum, and cortex reveal that the inhibition of glycogen phosphorolysis impacts not only glucose metabolism but also various other metabolic processes.

Keywords:  Behavioral tests; Brain aging; Glycogen phosphorylase (pyg); Hippocampus; Memory formation; Metabolomics

DOI:  https://doi.org/10.1038/s41598-024-74861-z
J Lipid Res. 2024 Oct 10. pii: S0022-2275(24)00172-X. [Epub ahead of print] 100667

Apolipoprotein B gene expression and regulation in relation to Alzheimer's disease pathophysiology.

Alzheimer's Disease Neuroimaging Initiative

  Apolipoprotein B (APOB), a receptor-binding protein present in cholesterol-rich lipoproteins, has been implicated in Alzheimer's disease (AD). High levels of APOB-containing low-density lipoproteins (LDL) are linked to the pathogenesis of both early-onset familial and late onset sporadic AD. Rare coding mutations in the APOB gene are associated with familial AD, suggesting a role for APOB-bound lipoproteins in the central nervous system. This research explores APOB gene regulation across the AD spectrum using four cohorts: BRAINEAC (elderly control brains), DBCBB (controls, AD brains), ROSMAP (controls, MCI, AD brains), and ADNI (control, MCI, AD clinical subjects). APOB protein levels, measured via mass spectrometry and ELISA, positively correlated with AD pathology indices and cognition, while APOB mRNA levels showed negative correlations. Brain APOB protein levels also correlated with cortical Aβ levels. A common coding variant in the APOB gene locus affected its expression but didn't impact AD risk or brain cholesterol concentrations, except for 24-S-hydroxycholesterol. Polymorphisms in the CYP27A1 gene, notably rs4674344, were associated with APOB protein levels. A negative correlation was observed between brain APOB gene expression and AD biomarker levels. CSF APOB correlated with Tau pathology in presymptomatic subjects, while cortical APOB was strongly associated with cortical Aβ deposition in late-stage AD. The study discusses the potential link between blood-brain barrier dysfunction and AD symptoms in relation to APOB neurobiology. Overall, APOB's involvement in lipoprotein metabolism appears to influence AD pathology across different stages of the disease.

Keywords:  Alzheimer’s disease; Apolipoproteins; Brain Lipids; Cholesterol; Lipoproteins/Receptors; Oxysterol; Transcription

DOI:  https://doi.org/10.1016/j.jlr.2024.100667
J Biol Chem. 2024 Oct 10. pii: S0021-9258(24)02376-7. [Epub ahead of print] 107874

Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model.

Da Lin, Sarah Kaye, Min Chen, Amogh Lyanna, Lihua Ye, Luke A Hammond, Jie Gao.

  Elucidating the intricate molecular mechanisms of Alzheimer's disease (AD) requires a multidimensional analysis incorporating various omics data. In this study, we employed transcriptome and proteome profiling of AppNL-G-F, a human APP knock-in model of amyloidosis, at the early and mid-stages of amyloid-beta (Aβ) pathology to delineate the impacts of Aβ deposition on brain cells. By contrasting AppNL-G-F mice with TREM2 (Triggering receptor expressed on myeloid cells 2) knockout models, our study further investigates the role of TREM2, a well-known AD risk gene, in influencing microglial responses to Aβ pathology. Our results highlight altered microglial states as a central feature of Aβ pathology, characterized by the significant upregulation of microglia-specific genes related to immune responses such as complement system and antigen presentation, and catabolic pathways such as phagosome formation and lysosome biogenesis. The absence of TREM2 markedly diminishes the induction of these genes, impairs Aβ clearance, and exacerbates dystrophic neurite formation. Importantly, TREM2 is required for the microglial engagement with Aβ plaques and the formation of compact Aβ plaque cores. Furthermore, this study reveals substantial disruptions in energy metabolism and protein synthesis, signaling a shift from anabolism to catabolism in response to Aβ deposition. This metabolic alteration, coupled with a decrease in synaptic protein abundance, occurs independently of TREM2, suggesting the direct effects of Aβ deposition on synaptic integrity and plasticity. In summary, our findings demonstrate altered microglial states and metabolic disruption following Aβ deposition, offering mechanistic insights into Aβ pathology and highlighting the potential of targeting these pathways in AD therapy.

Keywords:  Alzheimer’s disease; Microglia; brain metabolism; proteomics; transcriptomics

DOI:  https://doi.org/10.1016/j.jbc.2024.107874
Sci Rep. 2024 10 14. 14(1): 23992

Associations between elevated uric acid and brain imaging abnormalities in pediatric patients with methylmalonic acidemia under 5 years of age.

Mengmeng Du, Shengnan Wu, Yongxing Chen, Shuxian Yuan, Shijie Dong, Huizhen Wang, Haiyan Wei, Changlian Zhu.

  Methylmalonic acidemia (MMA) is the most common inborn organic acidemia, presenting multisystemic complications. Uric acid may have neurotoxic or neuroprotective effects due to its antioxidant or pro-inflammatory properties; however, its role in MMA brain injury remains unclear. We examined the correlation between the serum uric acid levels and brain imaging features of MMA. Data were collected from a cross-sectional study of 216 patients with MMA and 216 healthy matched controls aged 0-5 years in China. Serum uric acid levels were measured, and magnetic resonance imaging and computed tomography findings were retrieved from hospital records. Overall, 74.1% patients had brain abnormalities. Patients in the MMA group with abnormal brain imaging had higher serum uric acid levels than those in the MMA normal brain imaging and control groups. The area under the curve of serum uric acid was 0.74, 0.91, and 0.93 for MMA diagnosis with abnormal brain images, basal ganglia changes, and globus pallidus changes, respectively. Higher serum uric acid levels were independently associated with abnormal brain images. Children aged < 5 years with abnormal brain images in MMA exhibit elevated serum uric acid levels, serving as an effective auxiliary diagnostic indicator and independent risk factor for brain tissue injury.

Keywords:  Brain image; Brain structural injury; Children; Methylmalonic academia; Uric acid

DOI:  https://doi.org/10.1038/s41598-024-74710-z