bims-medebr 2023-05-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–05–14
37 papers selected by
Regina F. Fernández, Johns Hopkins University

Using stable isotope tracing to unravel the metabolic components of neurodegeneration: Focus on neuron-glia metabolic interactions.
16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.
High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.
Impaired Cholesterol Metabolism, Neurons, and Neuropsychiatric Disorders.
A tribute to Sebastián Cerdán and his key contributions to brain metabolism.
Fundamental Neurochemistry Review: Old brain stories- Influence of age and sex on the neurodegeneration-associated lipid changes.
In situ microwave fixation provides an instantaneous snapshot of the brain metabolome.
Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2 , and pO2.
Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.
Ketogenic diet-responsive drug-resistant epilepsy in a case of asparagine synthetase deficiency with a novel compound heterozygous missense variant.
β-arrestin1 regulates astrocytic reactivity via Drp1-dependent mitochondrial fission: implications in postoperative delirium.
Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype.
Renewal of Oligodendrocyte Lineage Reverses Dysmyelination and CNS Neurodegeneration Through Corrected N-acetylaspartate Metabolism.
Lipid flipping in the omega-3 fatty-acid transporter.
Serine metabolism during differentiation of human iPSC-derived astrocytes.
Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.
The human microglial surveillant phenotype is preserved by de novo neurosteroidogenesis through the control of cholesterol homeostasis: Crucial role of 18 kDa Translocator Protein.
Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation.
MULTIPLE GENES ENCODING MITOCHONDRIAL RIBOSOMES ARE DOWNREGULATED IN BRAIN AND BLOOD SAMPLES OF INDIVIDUALS WITH SCHIZOPHRENIA.
Generation and characterization of a knock-in mouse model for Spastic Tetraplegia, Thin Corpus Callosum, and Progressive Microcephaly (SPATCCM).
Fasting ketone levels vary by age: implications for differentiating physiologic from pathologic ketotic hypoglycemia.
Rise and fall of peroxisomes during Alzheimer´s disease: a pilot study in human brains.
Maintenance of mitochondrial homeostasis for Alzheimer's disease: Strategies and challenges.
APOE expression and secretion are modulated by mitochondrial dysfunction.
Molecular changes in hippocampal energy metabolism in mice selectively bred for extremes in stress reactivity: relevance of mitochondrial dysfunction for affective disorders.
Lipid metabolism in dendritic cell biology.
Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs.
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.
X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus.
A second case of glutaminase hyperactivity: Expanding the phenotype with epilepsy.
NAPE-PLD deletion in stress-TRAPed neurons results in an anxiogenic phenotype.
Ketogenic Diet Alleviates Brain Iron Deposition and Cognitive Dysfunction via Nrf2-mediated Ferroptosis pathway in APP/PS1 Mouse.
Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2-related mitochondrial disease.
Systematic crosstalk in plasmalogen and diacyl lipid biosynthesis for their differential yet concerted molecular functions in the cell.
Impact of sex and serum lipids interaction on working memory: A large-scale brain networks study.
Neurometabolic changes in a rat pup model of type C hepatic encephalopathy depend on age at liver disease onset.
Author Correction: Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer's disease mouse model.

Neurobiol Dis. 2023 May 05. pii: S0969-9961(23)00159-6. [Epub ahead of print] 106145

Using stable isotope tracing to unravel the metabolic components of neurodegeneration: Focus on neuron-glia metabolic interactions.

Emil W Westi, Jens V Andersen, Blanca I Aldana.

  Disrupted brain metabolism is a critical component of several neurodegenerative diseases. Energy metabolism of both neurons and astrocytes is closely connected to neurotransmitter recycling via the glutamate/GABA-glutamine cycle. Neurons and astrocytes hereby work in close metabolic collaboration which is essential to sustain neurotransmission. Elucidating the mechanistic involvement of altered brain metabolism in disease progression has been aided by the advance of techniques to monitor cellular metabolism, in particular by mapping metabolism of substrates containing stable isotopes, a technique known as isotope tracing. Here we review key aspects of isotope tracing including advantages, drawbacks and applications to different cerebral preparations. In addition, we narrate how isotope tracing has facilitated the discovery of central metabolic features in neurodegeneration with a focus on the metabolic cooperation between neurons and astrocytes.

Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Astrocytes; Brain energy metabolism; Huntington's disease; Mass spectrometry; Neurodegenerative disorders; Parkinson's disease

DOI:  https://doi.org/10.1016/j.nbd.2023.106145
Cell Rep. 2023 May 06. pii: S2211-1247(23)00496-5. [Epub ahead of print]42(5): 112485

16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.

Alexandria Béland-Millar, Alexia Kirby, Yen Truong, Julie Ouellette, Sozerko Yandiev, Khalil Bouyakdan, Chantal Pileggi, Shama Naz, Melissa Yin, Micaël Carrier, Pavel Kotchetkov, Marie-Kim St-Pierre, Marie-Ève Tremblay, Julien Courchet, Mary-Ellen Harper, Thierry Alquier, Claude Messier, Adam J Shuhendler, Baptiste Lacoste.

  Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Keywords:  16p11.2 deletion; CP: Metabolism; CP: Neuroscience; autism; brain; endothelium; glucose; lactate; metabolism; mitochondrion; mouse

DOI:  https://doi.org/10.1016/j.celrep.2023.112485
J Cereb Blood Flow Metab. 2023 May 08. 271678X231173584

High-physiological and supra-physiological 1,2-13C2 glucose focal supplementation to the traumatised human brain.

Matthew G Stovell, Duncan J Howe, Eric P Thelin, Ibrahim Jalloh, Adel Helmy, Mathew R Guilfoyle, Peter Grice, Andrew Mason, Susan Giorgi-Coll, Clare N Gallagher, Michael P Murphy, David K Menon, T Adrian Carpenter, Peter J Hutchinson, Keri Lh Carpenter.

  How to optimise glucose metabolism in the traumatised human brain remains unclear, including whether injured brain can metabolise additional glucose when supplied. We studied the effect of microdialysis-delivered 1,2-13C2 glucose at 4 and 8 mmol/L on brain extracellular chemistry using bedside ISCUSflex, and the fate of the 13C label in the 8 mmol/L group using high-resolution NMR of recovered microdialysates, in 20 patients. Compared with unsupplemented perfusion, 4 mmol/L glucose increased extracellular concentrations of pyruvate (17%, p = 0.04) and lactate (19%, p = 0.01), with a small increase in lactate/pyruvate ratio (5%, p = 0.007). Perfusion with 8 mmol/L glucose did not significantly influence extracellular chemistry measured with ISCUSflex, compared to unsupplemented perfusion. These extracellular chemistry changes appeared influenced by the underlying metabolic states of patients' traumatised brains, and the presence of relative neuroglycopaenia. Despite abundant 13C glucose supplementation, NMR revealed only 16.7% 13C enrichment of recovered extracellular lactate; the majority being glycolytic in origin. Furthermore, no 13C enrichment of TCA cycle-derived extracellular glutamine was detected. These findings indicate that a large proportion of extracellular lactate does not originate from local glucose metabolism, and taken together with our earlier studies, suggest that extracellular lactate is an important transitional step in the brain's production of glutamine.

Keywords:  1,2-13C2 glucose; Brain metabolism; NMR; microdialysis; traumatic brain injury (human)

DOI:  https://doi.org/10.1177/0271678X231173584
Exp Neurobiol. 2023 Apr 30. 32(2): 57-67

Impaired Cholesterol Metabolism, Neurons, and Neuropsychiatric Disorders.

So Yeong Cheon.

  Cholesterol metabolism plays an essential role in cellular functions (including as a component of the plasma membrane, as an energy source, and in hormone production) under normal conditions. Dysregulated cholesterol metabolism causes a wide spectrum of pathological conditions, leading to neuropsychiatric disorders, such as anxiety and depression. In addition, patients with neuropsychiatric disorders also have impaired cholesterol metabolism. Therefore, metabolic disturbances are closely associated with the neuropsychiatric disorders. Although immune disturbance, neuroinflammation, a dysregulated neurotransmitter system, and oxidative stress have been suggested as pathophysiology of neuropsychiatric disorders, dysregulation of cholesterol metabolism is also found in patients with psychiatric diseases. As expected, patients with mental illness appear to be at risk of metabolic disorders, including metabolic syndrome, in which cholesterol influences altered neuronal homeostasis, such as neuronal cell toxicity, neuronal cell death, and neuronal structures and functions, including synaptogenesis, neurogenesis, axonogenesis, and action potential. Therefore, reversing impaired or abnormal cholesterol metabolism may help restore neuronal injury found in mental illness. This review is aimed to discuss the links between cholesterol metabolism impairment and neuropsychiatric disorders and provides insights into neuronal dysfunction due to abnormal cholesterol metabolism in neuropsychiatric disorders.

Keywords:  Anxiety disorders; Cholesterol; Major depressive disorders; Neurons; Neurotransmission; Synapse

DOI:  https://doi.org/10.5607/en23010
J Neurochem. 2023 May 11.

A tribute to Sebastián Cerdán and his key contributions to brain metabolism.

Jorgina Satrustegui, Pilar López Larrubia, Tiago B Rodrigues, In-Young Choi, Mary C McKenna.

  This is a tribute to Sebastián Cerdán, a brilliant and innovative NMR spectroscopist whose studies contributed greatly to the fundamental information to the understanding of brain metabolism, particularly in regard to multinuclear magnetic resonance spectroscopy (MRS) techniques. Sebastián Cerdán sadly passed away in May 2022. He was a wonderful mentor and colleague who will be greatly missed.

Keywords:  MRS; NMR; Sebastian Cerdan; metabolism; pyruvate recycling pathway

DOI:  https://doi.org/10.1111/jnc.15828
J Neurochem. 2023 May 10.

Fundamental Neurochemistry Review: Old brain stories- Influence of age and sex on the neurodegeneration-associated lipid changes.

GOING-FWD Consortium

  Brain aging is a naturally occurring process resulting in the decline of cognitive functions and increased vulnerability to develop age-associated disorders. Fluctuation in lipid species is crucial for normal brain development and function. However, impaired lipid metabolism and changes in lipid composition in the brain have been increasingly recognized to play a crucial role in physiological aging, as well as in several neurodegenerative diseases. In the last decades, the role of sexual dimorphism in the vulnerability to develop age-related neurodegeneration has increased. However, further studies are warranted for detailed assessment to how age, sex and additional non biological factors may influence the lipid changes in brains. The aim of this work is to address the presence of sex differences in the brain lipid changes that occur along aging, and in the two most common age-related neurodegenerative disorders (Alzheimer's and Parkinson's disease). We included the studies that assessed lipid-related alterations in the brain of both humans and experimental models. Additionally, we explored the influence of sex on lipid-lowering therapies. We conclude that sex exerts a notable effect on lipid modifications occurring with age and neurodegeneration, and in the lipid-reducing interventions. Therefore, the application of sex as experimental variable is strongly encouraged for future research in the field towards precision medicine approach.

Keywords:  Alzheimer's disease; Lipids; Parkinson's disease; aging; sex; statins

DOI:  https://doi.org/10.1111/jnc.15834
Cell Rep Methods. 2023 04 24. 3(4): 100455

In situ microwave fixation provides an instantaneous snapshot of the brain metabolome.

Jelena A Juras, Madison B Webb, Lyndsay E A Young, Kia H Markussen, Tara R Hawkinson, Michael D Buoncristiani, Kayli E Bolton, Peyton T Coburn, Meredith I Williams, Lisa P Y Sun, William C Sanders, Ronald C Bruntz, Lindsey R Conroy, Chi Wang, Matthew S Gentry, Bret N Smith, Ramon C Sun.

  Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these postmortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high-power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the tricarboxylic acid (TCA) cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation for more accurate studies of brain metabolism in rodent models.

Keywords:  brain metabolism; isotope tracing; microwave fixation; regional metabolism; type 1 diabetes

DOI:  https://doi.org/10.1016/j.crmeth.2023.100455
J Neurochem. 2023 May 07.

Neurovascular coupling is optimized to compensate for the increase in proton production from nonoxidative glycolysis and glycogenolysis during brain activation and maintain homeostasis of pH, pCO2 , and pO2.

Mauro DiNuzzo, Gerald A Dienel, Kevin L Behar, Ognen A Petroff, Helene Benveniste, Fahmeed Hyder, Federico Giove, Shalom Michaeli, Silvia Mangia, Suzana Herculano-Houzel, Douglas L Rothman.

  During transient brain activation cerebral blood flow (CBF) increases substantially more than cerebral metabolic rate of oxygen consumption (CMRO2 ) resulting in blood hyperoxygenation, the basis of BOLD fMRI contrast. Explanations for the high CBF vs. CMRO2 slope, termed neurovascular coupling (NVC) constant, focused on maintainenance of tissue oxygenation to support mitochondrial ATP production. However, paradoxically the brain has a 3-fold lower oxygen extraction fraction (OEF) than other organs with high energy requirements, like heart and muscle during exercise. Here, we hypothesize that the NVC constant and the capillary oxygen mass transfer coefficient (which in combination determine OEF) are co-regulated during activation to maintain simultaneous homeostasis of pH and partial pressure of CO2 and O2 (pCO2 and pO2 ). To test our hypothesis, we developed an arteriovenous flux balance model for calculating blood and brain pH, pCO2 , and pO2 as a function of baseline OEF (OEF0 ), CBF, CMRO2 , and proton production by nonoxidative metabolism coupled to ATP hydrolysis. Our model was validated against published brain arteriovenous difference studies and then used to calculate pH, pCO2, and pO2 in activated human cortex from published calibrated fMRI and PET measurements. In agreement with our hypothesis, calculated pH, pCO2, and pO2 remained close to constant independently of CMRO2 in correspondence to experimental measurements of NVC and OEF0 . We also found that the optimum values of the NVC constant and OEF0 that ensure simultaneous homeostasis of pH, pCO2, and pO2 were remarkably similar to their experimental values. Thus, the high NVC constant is overall determined by proton removal by CBF due to increases in nonoxidative glycolysis and glycogenolysis. These findings resolve the paradox of the brain's high CBF yet low OEF during activation, and may contribute to explaining the vulnerability of brain function to reductions in blood flow and capillary density with aging and neurovascular disease.

Keywords:  aerobic glycolysis; brain activation; cerebral lactate; glucose sparing by glycogenolysis; homeostasis; neurovascular coupling

DOI:  https://doi.org/10.1111/jnc.15839
Neurotox Res. 2023 May 10.

Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.

Shubhada V Mangrulkar, Nitu L Wankhede, Mayur B Kale, Aman B Upaganlawar, Brijesh G Taksande, Milind J Umekar, Md Khalid Anwer, Hamad Ghaleb Dailah, Syam Mohan, Tapan Behl.

  Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.

Keywords:  Fission; Fusion; Mitochondrial dysfunction; Mitochondrial medicine; Mitochondrial quality control; Oxidative stress

DOI:  https://doi.org/10.1007/s12640-023-00647-2
Clin Neurol Neurosurg. 2023 May 08. pii: S0303-8467(23)00188-9. [Epub ahead of print]230 107772

Ketogenic diet-responsive drug-resistant epilepsy in a case of asparagine synthetase deficiency with a novel compound heterozygous missense variant.

Mert Altıntaş, Miraç Yıldırım, Çiğdem İlter Uçar, Engin Köse, Ömer Bektaş, Serap Teber.

  Asparagine synthetase deficiency (ASNSD) is a rare autosomal recessive neurometabolic disorder caused by homozygous or compound heterozygous mutations in the ASNS gene. Most of the patients have early-onset intractable seizures. A 7-year-old boy was first admitted to our clinic with intractable febrile and afebrile seizures that started when he was 6 months old. He had axial hypotonia with spastic quadriparesis, mild facial dysmorphism, and acquired microcephaly at 1 year-old. Metabolic tests showed a borderline-low serum asparagine level. The electroencephalogram demonstrated epileptic discharges with a high incidence of multifocal spike-wave activity. Brain MRI showed mild cerebral atrophy. His seizures continued despite combinations of multiple antiseizure agents. Whole-exome sequencing (WES) revealed a novel compound heterozygous missense variant of the ASNS gene, and the variants were confirmed by Sanger sequencing. He was started on a ketogenic diet at five years and six months of age. In the first month of the ketogenic diet, we observed that the frequency of seizures significantly decreased. He showed a remarkable improvement in seizures and milder improvement in cognitive skills. To our knowledge, our case is the first report describing significant improvement with a ketogenic diet in intractable seizures due to ASNSD.

Keywords:  Asparagine synthetase deficiency; Epilepsy; Ketogenic diet; Treatment; Whole-exome sequencing

DOI:  https://doi.org/10.1016/j.clineuro.2023.107772
J Neuroinflammation. 2023 May 11. 20(1): 113

β-arrestin1 regulates astrocytic reactivity via Drp1-dependent mitochondrial fission: implications in postoperative delirium.

Fuzhou Hua, Hong Zhu, Wen Yu, Qingcui Zheng, Lieliang Zhang, Weidong Liang, Yue Lin, Fan Xiao, Pengcheng Yi, Yanhong Xiong, Yao Dong, Hua Li, Lanran Fang, Hailin Liu, Jun Ying, Xifeng Wang.

  Postoperative delirium (POD) is a frequent and debilitating complication, especially amongst high risk procedures, such as orthopedic surgery. This kind of neurocognitive disorder negatively affects cognitive domains, such as memory, awareness, attention, and concentration after surgery; however, its pathophysiology remains unknown. Multiple lines of evidence supporting the occurrence of inflammatory events have come forward from studies in human patients' brain and bio-fluids (CSF and serum), as well as in animal models for POD. β-arrestins are downstream molecules of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). As versatile proteins, they regulate numerous pathophysiological processes of inflammatory diseases by scaffolding with inflammation-linked partners. Here we report that β-arrestin1, one type of β-arrestins, decreases significantly in the reactive astrocytes of a mouse model for POD. Using β-arrestin1 knockout (KO) mice, we find aggravating effect of β-arrestin1 deficiency on the cognitive dysfunctions and inflammatory phenotype of astrocytes in POD model mice. We conduct the in vitro experiments to investigate the regulatory roles of β-arrestin1 and demonstrate that β-arrestin1 in astrocytes interacts with the dynamin-related protein 1 (Drp1) to regulate mitochondrial fusion/fission process. β-arrestin1 deletion cancels the combination of β-arrestin1 and cellular Drp1, thus promoting the translocation of Drp1 to mitochondrial membrane to provoke the mitochondrial fragments and the subsequent mitochondrial malfunctions. Using β-arrestin1-biased agonist, cognitive dysfunctions of POD mice and pathogenic activation of astrocytes in the POD-linked brain region are reduced. We, therefore, conclude that β-arrestin1 is a promising target for the understanding of POD pathology and development of POD therapeutics.

Keywords:  Astrocytes; Mitochondrial fission; Neuroinflammation; Postoperative delirium; β-Arrestins

DOI:  https://doi.org/10.1186/s12974-023-02794-x
eNeuro. 2023 Apr;pii: ENEURO.0376-22.2023. [Epub ahead of print]10(4):

Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype.

Jin Hee Sung, Yang Ou, Steven W Barger.

  The apolipoprotein E gene (APOE) confers the greatest genetic risk factor for Alzheimer's disease (AD), wherein the ε4 allele confers an elevated risk compared with the ε3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or ApoE4 (ApoE-TR mice). Such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without amyloid β-peptide (Aβ) accumulation. We crossed ApoE3-TR and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42 In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and in membrane translocation of astrocytic glucose transporter 1 (GLUT1). Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects because of a trend toward perturbation of the baseline values.

Keywords:  Alzheimer’s disease; amyloid β-peptide; apolipoprotein E; glucose; insulin; microtubule-associated protein Tau

DOI:  https://doi.org/10.1523/ENEURO.0376-22.2023
Prog Neurobiol. 2023 May 04. pii: S0301-0082(23)00060-6. [Epub ahead of print] 102460

Renewal of Oligodendrocyte Lineage Reverses Dysmyelination and CNS Neurodegeneration Through Corrected N-acetylaspartate Metabolism.

Anoushka Lotun, Danning Li, Hongxia Xu, Qin Su, Serafettin Tuncer, Julio Sanmiguel, Morgan Mooney, Christina E Baer, Russell Ulbrich, Stephen J Eyles, Lara Strittmatter, Lawrence J Hayward, Dominic J Gessler, Guangping Gao.

  Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these myelination and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.

Keywords:  AAV; CNS; Canavan disease; Demyelination; Gene therapy; neurodegeneration

DOI:  https://doi.org/10.1016/j.pneurobio.2023.102460
Nat Commun. 2023 May 08. 14(1): 2571

Lipid flipping in the omega-3 fatty-acid transporter.

Chi Nguyen, Hsiang-Ting Lei, Louis Tung Faat Lai, Marc J Gallenito, Xuelang Mu, Doreen Matthies, Tamir Gonen.

Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.

DOI: https://doi.org/10.1038/s41467-023-37702-7
FEBS J. 2023 May 11.

Serine metabolism during differentiation of human iPSC-derived astrocytes.

Farida Tripodi, Zoraide Motta, Giulia Murtas, Valentina Rabattoni, Simona Nonnis, Francesca Grassi Scalvini, Anna Maria Rinaldi, Roberto Rizzi, Claudia Bearzi, Beatrice Badone, Silvia Sacchi, Gabriella Tedeschi, Elisa Maffioli, Paola Coccetti, Loredano Pollegioni.

  Astrocytes are essential players in development and functions, being particularly relevant as regulators of brain energy metabolism, ionic homeostasis, and synaptic transmission. They are also the major source of L-serine in the brain, which is synthesized from the glycolytic intermediate 3-phosphoglycerate through the phosphorylated pathway. L-serine is the precursor of the two main co-agonists of the N-methyl-D-aspartate receptor, glycine and D-serine. Strikingly, dysfunctions in both L- and D-serine metabolism are associated with neurological and psychiatric disorders. Here, we exploited a differentiation protocol, based on the generation of human mature astrocytes from neural stem cells, and investigated the modification of the proteomic and metabolomic profile during the differentiation process. We show that differentiated astrocytes are more similar to mature rather than to reactive ones, and that axogenesis and pyrimidine metabolism increase up to 30 days along with the folate cycle and sphingolipid metabolism. Consistent with the proliferation and cellular maturation processes that are taking place, also the intracellular level of L-serine, glycine, threonine, L- and D-aspartate (which level is unexpectedly higher than that of D-serine) show the same biosynthetic time course. A significant utilization of L-serine from the medium is apparent while glycine is first consumed and then released with a peak at 30 days, parallel to its intracellular level. These results underline how metabolism changes during astrocytes differentiation, highlight that D-serine synthesis is restricted in differentiated astrocytes, and provide a valuable model for developing potential novel therapeutic approaches to address brain diseases, especially the ones related to serine metabolism alterations.

Keywords:  D-serine; amino acid metabolism; metabolomics; neurotransmission; proteomics

DOI:  https://doi.org/10.1111/febs.16816
Hum Mol Genet. 2023 May 10. pii: ddad076. [Epub ahead of print]

Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.

Xue-Jun Zhao, A I-Walid Mohsen, Stephanie Mihalik, Keaton Solo, Shakuntala Basu, Ermal Aliu, Huifang Shi, Catherine Kochersberger, Anuradha Karunanidhi, Clinton Van't Land, Kimberly A Coughlan, Summar Siddiqui, Lisa M Rice, Shawn Hillier, Eleonora Guadagnin, Christine DeAntonis, Paloma H Giangrande, Paolo G V Martini, Jerry Vockley.

  Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart, and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.

Keywords:   Acadm−/− mouse; fatty acid oxidation disorders; fibroblasts; mRNA therapy; medium-chain acyl-CoA dehydrogenase deficiency; mitochondria

DOI:  https://doi.org/10.1093/hmg/ddad076
Biochim Biophys Acta Mol Basis Dis. 2023 May 09. pii: S0925-4439(23)00117-5. [Epub ahead of print] 166751

The human microglial surveillant phenotype is preserved by de novo neurosteroidogenesis through the control of cholesterol homeostasis: Crucial role of 18 kDa Translocator Protein.

Elisa Angeloni, Lorenzo Germelli, Laura Marchetti, Eleonora Da Pozzo, Chiara Tremolanti, Christian H Wetzel, Emma Baglini, Sabrina Taliani, Federico Da Settimo, Claudia Martini, Barbara Costa.

  Neurodegenerative disease-associated microglia commonly exhibit harmful cholesterol accumulation that impairs their ability to resolve the neuroinflammatory response, contributing to disease onset and progression. Neurosteroids, whose levels have been often found significantly altered in brain diseases, are the most potent endogenous anti-inflammatory molecules exerting beneficial effects on activities of brain cells, including microglia. For the first time, the impact of neurosteroidogenesis on cholesterol homeostasis for the immune surveillance phenotype maintenance was investigated in a human microglia in vitro model. To enhance and inhibit neurosteroidogenesis, pharmacological stimulation and knock-down of 18 kDa Translocator Protein (TSPO), which is involved in the neurosteroidogenesis rate-limiting step, were used as experimental approaches, respectively. The obtained results point to an essential autocrine control of neurosteroidogenesis in orchestrating cholesterol trafficking in human microglia. TSPO pharmacological stimulation ensured cholesterol turnover by strengthening cholesterol efflux systems and preserving healthy immune surveillant phenotype. Conversely, TSPO knock-down induced an impairment of the controlled interplay among cholesterol synthesis, efflux, and metabolism mechanisms, leading to an excessive cholesterol accumulation and acquisition of a chronically activated dysfunctional phenotype. In this model, the exogenous neurosteroid administration restored proper the cholesterol clearance. The TSPO ability in promoting native neurosteroidogenesis opens the way to restore cholesterol homeostasis, and thus to maintain microglia proper functionality for the treatment of neuroinflammation-related brain diseases.

Keywords:  18 kDa Translocator Protein; Autocrine regulation; Cholesterol homeostasis; Surveillant microglia; TSPO ligand; de novo neurosteroidogenesis

DOI:  https://doi.org/10.1016/j.bbadis.2023.166751
Neurotherapeutics. 2023 May 08.

Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation.

Ana C Valencia-Olvera, Deebika Balu, Naomi Faulk, Aspasia Amiridis, Yueting Wang, Christine Pham, Eva Avila-Munoz, Jason M York, Gregory R J Thatcher, Mary Jo LaDu.

  APOE4, encoding apolipoprotein E4 (apoE4), is the greatest genetic risk factor for Alzheimer's disease (AD), compared to the common APOE3. While the mechanism(s) underlying APOE4-induced AD risk remains unclear, increasing the lipidation of apoE4 is an important therapeutic target as apoE4-lipoproteins are poorly lipidated compared to apoE3-lipoproteins. ACAT (acyl-CoA: cholesterol-acyltransferase) catalyzes the formation of intracellular cholesteryl-ester droplets, reducing the intracellular free cholesterol (FC) pool. Thus, inhibiting ACAT increases the FC pool and facilitates lipid secretion to extracellular apoE-containing lipoproteins. Previous studies using commercial ACAT inhibitors, including avasimibe (AVAS), as well as ACAT-knock out (KO) mice, exhibit reduced AD-like pathology and amyloid precursor protein (APP) processing in familial AD (FAD)-transgenic (Tg) mice. However, the effects of AVAS with human apoE4 remain unknown. In vitro, AVAS induced apoE efflux at concentrations of AVAS measured in the brains of treated mice. AVAS treatment of male E4FAD-Tg mice (5xFAD+/-APOE4+/+) at 6-8 months had no effect on plasma cholesterol levels or distribution, the original mechanism for AVAS treatment of CVD. In the CNS, AVAS reduced intracellular lipid droplets, indirectly demonstrating target engagement. Surrogate efficacy was demonstrated by an increase in Morris water maze measures of memory and postsynaptic protein levels. Amyloid-beta peptide (Aβ) solubility/deposition and neuroinflammation were reduced, critical components of APOE4-modulated pathology. However, there was no increase in apoE4 levels or apoE4 lipidation, while amyloidogenic and non-amyloidogenic processing of APP were significantly reduced. This suggests that the AVAS-induced reduction in Aβ via reduced APP processing was sufficient to reduce AD pathology, as apoE4-lipoproteins remained poorly lipidated.

Keywords:  ACAT-1; APOE4; APP processing; Alzheimer’s disease; Neuroinflammation; Oligomeric Aβ

DOI:  https://doi.org/10.1007/s13311-023-01375-3
World J Biol Psychiatry. 2023 May 09. 1-18

MULTIPLE GENES ENCODING MITOCHONDRIAL RIBOSOMES ARE DOWNREGULATED IN BRAIN AND BLOOD SAMPLES OF INDIVIDUALS WITH SCHIZOPHRENIA.

Gideon Bartal, Assif Yitzhaky, Aviv Segev, Libi Hertzberg.

   OBJECTIVES: Schizophrenia is a chronic, debilitating mental disorder whose pathophysiology is complex and not fully understood. Numerous studies suggest mitochondrial dysfunction may contribute to the development of schizophrenia. While mitochondrial ribosomes (mitoribosomes) are essential for proper mitochondrial functioning, their gene expression levels have not been studied yet in schizophrenia.
METHODS: We performed a systematic meta-analysis of the expression of 81 mitoribosomes subunits encoding genes, integrating ten brain samples datasets of patients with schizophrenia compared to healthy controls (overall 422 samples, 211 schizophrenia, and 211 controls). We also performed a meta-analysis of their expression in blood, integrating two blood sample datasets (overall 90 samples, 53 schizophrenia, and 37 controls).
RESULTS: Multiple mitoribosomes subunits were significantly downregulated in brain samples (18 genes) and in blood samples (11 genes) of individuals with schizophrenia, where two showed significant downregulation in both brain and blood, MRPL4 and MRPS7.
CONCLUSIONS: Our results support the accumulating evidence of impaired mitochondrial activity in schizophrenia. While further research is needed to validate mitoribosomes' role as biomarkers, this direction has the potential to promote patients' stratification and personalized treatment for schizophrenia.

Keywords:  Gene expression; MRPL; MRPS; Postmortem brain samples; biomarkers; schizophrenia

DOI:  https://doi.org/10.1080/15622975.2023.2211653
Res Sq. 2023 Apr 24. pii: rs.3.rs-2839029. [Epub ahead of print]

Generation and characterization of a knock-in mouse model for Spastic Tetraplegia, Thin Corpus Callosum, and Progressive Microcephaly (SPATCCM).

Megan L Ratz, Greg Leary, Andrea Grindeland, Derek Silvius, Joseph Guter, Michael P Kavanaugh, Teresa M Gunn.

SLC1A4 (solute carrier family 1 member 4, also referred to as ASCT1, Alanine/Serine/Cysteine/Threonine-preferring Transporter 1) is a sodium-dependent neutral amino acid transporter. It is highly expressed in many tissues, including the brain, where it is expressed primarily on astrocytes and plays key roles in neuronal differentiation and development, maintaining neurotransmitter homeostasis, and N-methyl-D-aspartate (NMDA) neurotransmission, through regulation of L- and D-serine. Mutations in SLC1A4 are associated with the rare autosomal recessive neurodevelopmental disorder spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM, OMIM 616657). Psychomotor development and speech are significantly impaired in these patients, and many develop seizures. We generated and characterized a knock-in mouse model for the most common mutant allele, which results in a single amino acid change (p.Glu256Lys, or E256K). Homozygous mutants had increased D-serine uptake in the brain, microcephaly, and thin corpus callosum and cortex layer 1. While p.E256K homozygotes showed some significant differences in exploratory behavior relative to wildtype mice, their performance in assays for motor coordination, endurance, learning, and memory was normal, and they showed no significant differences in long-term potentiation. Taken together, these results indicate that some aspects of SLC1A4 function in brain development are conserved between mice and humans, but the impact of the p.E256K mutation on cognition and motor function is minimal in mice.

DOI: https://doi.org/10.21203/rs.3.rs-2839029/v1
J Pediatr Endocrinol Metab. 2023 May 11.

Fasting ketone levels vary by age: implications for differentiating physiologic from pathologic ketotic hypoglycemia.

Komalben Parmar, Maua Mosha, David A Weinstein, Rebecca Riba-Wolman.

   OBJECTIVES: Ketone production is a physiological phenomenon that occurs during beta-oxidation of free fatty acids. Distinguishing physiologic ketosis from pathologic over-production/underutilization of ketones is critical as part of the diagnostic evaluation of disorders of carbohydrate metabolism, but there is limited literature on normal ketone production with fasting. Our aim is to measure fasting serum beta-hydroxybutyrate (BHB) concentrations in healthy children after an overnight fast.
METHODS: Children ≤18 years of age were prospectively recruited from elective procedures through our surgery centers. Exclusion criteria included a history of diabetes, hypopituitarism, adrenal, metabolic or inflammatory disorders, dietary restrictions, trauma, or use of medications that might affect blood glucose. Serum glucose, cortisol, and BHB were assessed after an overnight fast.
RESULTS: Data from 94 participants (mean 8.3 ± 5.7 years, 54 % male, 46 % female, were analyzed. Children ≤3 years of age (19) have significantly higher mean (0.40 ± 0.06 mmol/L) and median (0.4, IQR 0.2-0.6 mmol/L) BHB concentrations compared to children >3 years of age (75) with mean (0.21 ± 0.02 mmol/L) and median BHB (0.1, IQR 0.1-0.2 mmol/L) (p<0.0001). Fasting BHB levels of >1.0 mmol/L was rare (2 %, N=2) and 74 % (N=70) of participants had BHB levels <0.3 mmol/L.
CONCLUSIONS: BHB concentrations are significantly higher in young children (≤3 years of age) compared to older children. Fasting BHB levels >1.0 mmol/L are rare within our population and therefore may identify a value above which there may a greater concern for pathologic ketotic hypoglycemia. It is imperative to establish the normative range in children to differentiate physiological from pathological ketotic hypoglycemia.

Keywords:  beta-hydroxybutyrate; fasting ketosis; ketotic hypoglycemia; pathologic ketotic hypoglycemia; pediatrics, idiopathic ketotic hypoglycemia; physiological ketotic hypoglycemia

DOI:  https://doi.org/10.1515/jpem-2022-0589
Acta Neuropathol Commun. 2023 May 11. 11(1): 80

Rise and fall of peroxisomes during Alzheimer´s disease: a pilot study in human brains.

Eugen Semikasev, Barbara Ahlemeyer, Till Acker, Anne Schänzer, Eveline Baumgart-Vogt.

  Peroxisomes are eukaryotic organelles that rapidly change in number depending on the metabolic requirement of distinct cell types and tissues. In the brain, these organelles are essential for neuronal migration and myelination during development and their dysfunction is associated with age-related neurodegenerative diseases. Except for one study analysing ABCD3-positive peroxisomes in neurons of the frontal neocortex of Alzheimer disease (AD) patients, no data on other brain regions or peroxisomal proteins are available. In the present morphometric study, we quantified peroxisomes labelled with PEX14, a metabolism-independent peroxisome marker, in 13 different brain areas of 8 patients each either with low, intermediate or high AD neuropathological changes compared to 10 control patients. Classification of patient samples was based on the official ABC score. During AD-stage progression, the peroxisome density decreased in the area entorhinalis, parietal/occipital neocortex and cerebellum, it increased and in later AD-stage patients decreased in the subiculum and hippocampal CA3 region, frontal neocortex and pontine gray and it remained unchanged in the gyrus dentatus, temporal neocortex, striatum and inferior olive. Moreover, we investigated the density of catalase-positive peroxisomes in a subset of patients (> 80 years), focussing on regions with significant alterations of PEX14-positive peroxisomes. In hippocampal neurons, only one third of all peroxisomes contained detectable levels of catalase exhibiting constant density at all AD stages. Whereas the density of all peroxisomes in neocortical neurons was only half of the one of the hippocampus, two thirds of them were catalase-positive exhibiting increased levels at higher ABC scores. In conclusion, we observed spatiotemporal differences in the response of peroxisomes to different stages of AD-associated pathologies.

Keywords:  Catalase; Hippocampus; Neocortex; Neurodegenerative disorder; PEX14; Peroxisome; Pyramidal neurons

DOI:  https://doi.org/10.1186/s40478-023-01567-0
Redox Biol. 2023 May 06. pii: S2213-2317(23)00135-0. [Epub ahead of print]63 102734

Maintenance of mitochondrial homeostasis for Alzheimer's disease: Strategies and challenges.

Ying Han, Daozhou Liu, Ying Cheng, Qifeng Ji, Miao Liu, Bangle Zhang, Siyuan Zhou.

  Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and its early onset is closely related to mitochondrial energy metabolism. The brain is only 2% of body weight, but consumes 20% of total energy needs. Mitochondria are responsible for providing energy in cells, and maintaining their homeostasis ensures an adequate supply of energy to the brain. Mitochondrial homeostasis is constituted by mitochondrial quantity and quality control, which is dynamically regulated by mitochondrial energy metabolism, mitochondrial dynamics and mitochondrial quality control. Impaired energy metabolism of brain cells occurs early in AD, and maintaining mitochondrial homeostasis is a promising therapeutic target in the future. We summarized the mechanism of mitochondrial homeostasis in AD, its influence on the pathogenesis of early AD, strategies for maintaining mitochondrial homeostasis, and mitochondrial targeting strategies. This review concludes with the authors' opinions on future research and development for mitochondrial homeostasis of early AD.

Keywords:  Alzheimer's disease; Mitochondrial dynamics; Mitochondrial quality control; Mitochondrial targeting; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.redox.2023.102734
Elife. 2023 May 12. pii: e85779. [Epub ahead of print]12

APOE expression and secretion are modulated by mitochondrial dysfunction.

Meghan E Wynne, Oluwaseun Ogunbona, Alicia R Lane, Avanti Gokhale, Stephanie A Zlatic, Chongchong Xu, Zhexing Wen, Duc M Duong, Sruti Rayaprolu, Anna Ivanova, Eric A Ortlund, Eric B Dammer, Nicholas T Seyfried, Blaine R Roberts, Amanda Crocker, Vinit Shanbhag, Michael Petris, Nanami Senoo, Selvaraju Kandasamy, Steven Michael Claypool, Antoni Barrientos, Aliza Wingo, Thomas S Wingo, Srikant Rangaraju, Allan I Levey, Erica Werner, Victor Faundez.

  Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain, elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.

Keywords:  cell biology; human; neuroscience

DOI:  https://doi.org/10.7554/eLife.85779
Eur J Neurosci. 2023 May 11.

Molecular changes in hippocampal energy metabolism in mice selectively bred for extremes in stress reactivity: relevance of mitochondrial dysfunction for affective disorders.

Virginie Rappeneau, Prasanna Koti, Lars Wilmes, Regina Widner-Andrae, Karin Busch, Chadi Touma.

  Affective disorders, such as major depression, are frequently associated with metabolic disturbances involving mitochondria. Although dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is known to alter energy metabolism, the precise mechanisms linking stress and metabolic disturbances are not sufficiently understood. We used a mouse model of affective disorders to investigate the impact of a genetic predisposition for extremes in stress reactivity on behavioural and metabolic phenotypes as well as energy metabolism. Adult males of three independent mouse lines selectively bred for high, intermediate or low HPA axis reactivity were tested for exploratory and locomotor activity as well as stress-coping behaviour. Additionally, basal and stress-induced plasma corticosterone levels, body weight, food intake and body composition were measured. At the molecular level, the hippocampal transcriptome was analysed using microarray, serial analysis of gene expression and qRT-PCR. Finally, mitochondrial DNA copy number, damages and mitochondrial respiration were assessed. We found clear effects of the differential stress reactivity on the behavioural, morphometric and metabolic measures. Remarkably, the hyperactive behavioural and neuroendocrine stress-coping style of High Reactivity mice was associated with significant changes in the expression of an extended list of genes involved in energy metabolism and several mitochondrial functions. Yet, only minor changes were found in mitochondrial DNA copy number, damages and respiration. Thus, our findings support a prominent role of glucocorticoids in shaping the major endophenotypes of the stress reactivity mouse model and contribute towards understanding the important role of HPA axis dysregulation and changes in energy metabolism in the pathophysiology of affective disorders.

Keywords:  energy metabolism; hippocampus; major depression; mitochondria; mouse model; stress

DOI:  https://doi.org/10.1111/ejn.16044
Immunol Rev. 2023 May 12.

Lipid metabolism in dendritic cell biology.

Zhiyuan You, Hongbo Chi.

  Dendritic cells (DCs) are innate immune cells that detect and process environmental signals and communicate them with T cells to bridge innate and adaptive immunity. Immune signals and microenvironmental cues shape the function of DC subsets in different contexts, which is associated with reprogramming of cellular metabolic pathways. In addition to integrating these extracellular cues to meet bioenergetic and biosynthetic demands, cellular metabolism interplays with immune signaling to shape DC-dependent immune responses. Emerging evidence indicates that lipid metabolism serves as a key regulator of DC responses. Here, we summarize the roles of fatty acid and cholesterol metabolism, as well as selective metabolites, in orchestrating the functions of DCs. Specifically, we highlight how different lipid metabolic programs, including de novo fatty acid synthesis, fatty acid β oxidation, lipid storage, and cholesterol efflux, influence DC function in different contexts. Further, we discuss how dysregulation of lipid metabolism shapes DC intracellular signaling and contributes to the impaired DC function in the tumor microenvironment. Finally, we conclude with a discussion on key future directions for the regulation of DC biology by lipid metabolism. Insights into the connections between lipid metabolism and DC functional specialization may facilitate the development of new therapeutic strategies for human diseases.

Keywords:  cholesterol; dendritic cells; fatty acid; innate immunity; lipid metabolism; lipid metabolites

DOI:  https://doi.org/10.1111/imr.13215
Brain. 2023 May 12. pii: awad158. [Epub ahead of print]

Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs.

Adriana P Rebelo, Pedro J Tomaselli, Jessica Medina, Ying Wang, Maike Dohrn, Eva Nyvltova, Matt Denzi, Mark Garrett, Sean Smith, Alan Pestronk, ChengCheng Li, Ariel Ruiz, Elizabeth Jacobs, Shawna M E Feely, Marcondes C França, Marcus V Gomes, Diogo Santos, Surinder Kumar, David B Lombard, Mario Saporta, Siegfried Hekimi, Antonio Barrientos, Conrad Weihl, Michael Shy, Wilson Marques, Stephan Zuchner.

  COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary coenzyme Q10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder. We identified COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy (dHMN) with upper neuron involvement, expending the clinical phenotype associated with defects in this gene. A recurrent p.Met1? change was identified in five families from Brazil with evidence of a founder effect. Fibroblasts isolated from patients revealed a substantial depletion of COQ7 protein levels, indicating protein instability leading to loss of enzyme function. HPLC assay showed that fibroblasts from patients had reduced levels of CoQ10, and abnormal accumulation of the biosynthetic precursor DMQ10. Accordingly, fibroblasts from patients displayed significantly decreased oxygen consumption rates in patients, suggesting mitochondrial respiration deficiency. iPSC-derived motor neurons from patient fibroblasts showed significantly increased levels of extracellular neurofilament light protein, indicating axonal degeneration. Our findings indicate a molecular pathway involving CoQ10 biosynthesis deficiency and mitochondrial dysfunction in patients with dHMN. Further studies will be important to evaluate the potential benefits of CoQ10 supplementation in the clinical outcome of the disease.

Keywords:  Charcot-Marie-Tooth disease; CoQ10; hereditary motor neuropathy; mitochondria; motor neuron

DOI:  https://doi.org/10.1093/brain/awad158
bioRxiv. 2023 Apr 29. pii: 2023.04.28.538740. [Epub ahead of print]

APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size.

Ian A Windham, Joey V Ragusa, E Diane Wallace, Colby H Wagner, Kristen K White, Sarah Cohen.

The E4 variant of APOE strongly predisposes individuals to late-onset Alzheimer's disease. We demonstrate that in response to neutral lipid synthesis, apolipoprotein E (APOE) in astrocytes can avoid translocation into the ER lumen and traffic to lipid droplets (LDs) via membrane bridges at ER-LD contacts. APOE knockdown promotes fewer, larger LDs containing more unsaturated triglyceride. This LD size distribution phenotype was rescued by chimeric APOE that targets only LDs. APOE4 - expressing astrocytes also form a small number of large LDs enriched in unsaturated triglyceride. Additionally, the larger LDs in APOE4 cells exhibit impaired turnover and increased sensitivity to lipid peroxidation. Our data indicate that APOE plays a previously unrecognized role as an LD surface protein that regulates LD size and composition. APOE4 is a toxic gain of function variant that causes aberrant LD composition and morphology. We propose that APOE4 astrocytes with large, unsaturated LDs are sensitized to lipid peroxidation or lipotoxicity, which could contribute to Alzheimer's disease risk.
Summary: Windham et al . discover that APOE in astrocytes can traffic to lipid droplets (LDs), where it modulates LD composition and size. Astrocytes expressing the Alzheimer's risk variant APOE4 form large LDs with impaired turnover and increased peroxidation sensitivity.

DOI: https://doi.org/10.1101/2023.04.28.538740
Prenat Diagn. 2023 May 09.

X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus.

Laura M Tanner, Olli Tynninen, Kirsi Piippo, Antti M Puhakka.

We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11+2 weeks of pregnancy. At 20+0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/pd.6349
JIMD Rep. 2023 May;64(3): 217-222

A second case of glutaminase hyperactivity: Expanding the phenotype with epilepsy.

Lynne Rumping, Petra J W Pouwels, Nicole I Wolf, Holger Rehmann, Mirjam M C Wamelink, Quinten Waisfisz, Judith J M Jans, Hubertus C M T Prinsen, Jiddeke M van de Kamp, Peter M van Hasselt.

  Glutaminase (GLS) hyperactivity was first described in 2019 in a patient with profound developmental delay and infantile cataract. Here, we describe a 4-year-old boy with GLS hyperactivity due to a de novo heterozygous missense variant in GLS, detected by trio whole exome sequencing. This boy also exhibits developmental delay without dysmorphic features, but does not have cataract. Additionally, he suffers from epilepsy with tonic clonic seizures. In line with the findings in the previously described patient with GLS hyperactivity, in vivo 3 T magnetic resonance spectroscopy (MRS) of the brain revealed an increased glutamate/glutamine ratio. This increased ratio was also found in urine with UPLC-MS/MS, however, inconsistently. This case indicates that the phenotypic spectrum evoked by GLS hyperactivity may include epilepsy. Clarifying this phenotypic spectrum is of importance for the prognosis and identification of these patients. The combination of phenotyping, genetic testing, and metabolic diagnostics with brain MRS and in urine is essential to identify new patients with GLS hyperactivity and to further extend the phenotypic spectrum of this disease.

Keywords:  GLS hyperactivity; epilepsy; glutamate; high‐throughput sequencing; phenotypic spectrum

DOI:  https://doi.org/10.1002/jmd2.12359
Transl Psychiatry. 2023 05 06. 13(1): 152

NAPE-PLD deletion in stress-TRAPed neurons results in an anxiogenic phenotype.

Margaryta Tevosian, Hristo Todorov, Ermelinda Lomazzo, Laura Bindila, Natsuo Ueda, Davide Bassetti, Davide Warm, Sergei Kirischuk, Heiko J Luhmann, Susanne Gerber, Beat Lutz.

Anandamide (AEA) is an endogenous ligand of the cannabinoid CB1 and CB2 receptors, being a component of the endocannabinoid signaling system, which supports the maintenance or regaining of neural homeostasis upon internal and external challenges. AEA is thought to play a protective role against the development of pathological states after prolonged stress exposure, including depression and generalized anxiety disorder. Here, we used the chronic social defeat (CSD) stress as an ethologically valid model of chronic stress in male mice. We characterized a genetically modified mouse line where AEA signaling was reduced by deletion of the gene encoding the AEA synthesizing enzyme N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) specifically in neurons activated at the time of CSD stress. One week after the stress, the phenotype was assessed in behavioral tests and by molecular analyses. We found that NAPE-PLD deficiency in neurons activated during the last three days of CSD stress led to an increased anxiety-like behavior. Investigating the molecular mechanisms underlying this phenotype may suggest three main altered pathways to be affected: (i) desensitization of the negative feedback loop of the hypothalamic-pituitary-adrenal axis, (ii) disinhibition of the amygdala by the prefrontal cortex, and (iii) altered neuroplasticity in the hippocampus and prefrontal cortex.

DOI: https://doi.org/10.1038/s41398-023-02448-9
Brain Res. 2023 May 08. pii: S0006-8993(23)00175-0. [Epub ahead of print] 148404

Ketogenic Diet Alleviates Brain Iron Deposition and Cognitive Dysfunction via Nrf2-mediated Ferroptosis pathway in APP/PS1 Mouse.

Yaya Qin, Dazhang Bai, Ming Tang, Ming Zhang, Li Zhao, Jia Li, Rui Yang, Guohui Jiang.

  Progressive cognitive decline and increased brain iron deposition with age are important features of Alzheimer's disease. Previous studies have found that the short-term ketogenic diet has neuroprotective effects in a variety of neurodegenerative diseases, but the effects of an early and long-term ketogenic diet on brain iron content and cognition of Alzheimer's disease have not been reported. In our study, 8-week-old APP/PS1 mice were given a 12-month ketogenic or standard diet, while C57BL/6 mice matched with the age and genetic background of APP/PS1 mice were used as normal controls to be given a standard diet for the same length of time. We found that 12 months of an early ketogenic diet improved the impaired learning and memory ability of APP/PS1 mice. The improvement of cognitive function may be related to the reduction of amyloid-beta deposition and neuronal ferroptosis. The mechanism was achieved by the regulation of ferroptosis-related pathways after activation of nuclear factor erythroid 2-related factor 2 by ketogenic diet-induced elevated β-hydroxybutyrate. In addition, blood biochemical results showed that compared with the standard diet group of the disease, although the early and long-term ketogenic diet increased blood lipids to some extent, it seemed to reduce liver, renal, and myocardial damage caused by genetic differences. This will provide a piece of positive evidence for the early and long-term use of ketogenic diets in people at risk of Alzheimer's disease.

Keywords:  Alzheimer's disease; brain iron deposition; cognitive dysfunction; ferroptosis; ketogenic diet

DOI:  https://doi.org/10.1016/j.brainres.2023.148404
JIMD Rep. 2023 May;64(3): 223-232

Severe neonatal onset neuroregression with paroxysmal dystonia and apnoea: Expanding the phenotypic and genotypic spectrum of CARS2-related mitochondrial disease.

Jessie Poquérusse, Melinda Nolan, David R Thorburn, Johan L K Van Hove, Marisa W Friederich, Donald R Love, Juliet Taylor, Christopher A Powell, Michal Minczuk, Russell G Snell, Klaus Lehnert, Emma Glamuzina, Jessie C Jacobsen.

  Disorders of mitochondrial function are a collectively common group of genetic diseases in which deficits in core mitochondrial translation machinery, including aminoacyl tRNA synthetases, are key players. Biallelic variants in the CARS2 gene (NM_024537.4), which encodes the mitochondrial aminoacyl-tRNA synthetase for cysteine (CARS2, mt-aaRScys; MIM*612800), result in childhood onset epileptic encephalopathy and complex movement disorder with combined oxidative phosphorylation deficiency (MIM#616672). Prior to this report, eight unique pathogenic variants in the CARS2 gene had been reported in seven individuals. Here, we describe a male who presented in the third week of life with apnoea. He rapidly deteriorated with paroxysmal dystonic crises and apnoea resulting in death at 16 weeks. He had no evidence of seizure activity or multisystem disease and had normal brain imaging. Skeletal muscle biopsy revealed a combined disorder of oxidative phosphorylation. Whole-exome sequencing identified biallelic variants in the CARS2 gene: one novel (c.1478T>C, p.Phe493Ser), and one previously reported (c.655G>A, p.Ala219Thr; rs727505361). Northern blot analysis of RNA isolated from the patient's fibroblasts confirmed a clear defect in aminoacylation of the mitochondrial tRNA for cysteine (mt-tRNACys). To our knowledge, this is the earliest reported case of CARS2 deficiency with severe, early onset dystonia and apnoea, without epilepsy.

Keywords:  CARS2; mitochondrial disorders; neurodevelopmental disorder; tRNA synthetases; whole‐exome sequencing

DOI:  https://doi.org/10.1002/jmd2.12360
Prog Lipid Res. 2023 May 09. pii: S0163-7827(23)00024-3. [Epub ahead of print] 101234

Systematic crosstalk in plasmalogen and diacyl lipid biosynthesis for their differential yet concerted molecular functions in the cell.

Tomohiro Kimura, Atsuko K Kimura, Richard M Epand.

  Plasmalogen is a major phospholipid of mammalian cell membranes. Recently it is becoming evident that the sn-1 vinyl-ether linkage in plasmalogen, contrasting to the ester linkage in the counterpart diacyl glycerophospholipid, yields differential molecular characteristics for these lipids especially related to hydrocarbon-chain order, so as to concertedly regulate biological membrane processes. A role played by NMR in gaining information in this respect, ranging from molecular to tissue levels, draws particular attention. We note here that a broad range of enzymes in de novo synthesis pathway of plasmalogen commonly constitute that of diacyl glycerophospholipid. This fact forms the basis for systematic crosstalk that not only controls a quantitative balance between these lipids, but also senses a defect causing loss of lipid in either pathway for compensation by increase of the counterpart lipid. However, this inherent counterbalancing mechanism paradoxically amplifies imbalance in differential effects of these lipids in a diseased state on membrane processes. While sharing of enzymes has been recognized, it is now possible to overview the crosstalk with growing information for specific enzymes involved. The overview provides a fundamental clue to consider cell and tissue type-dependent schemes in regulating membrane processes by plasmalogen and diacyl glycerophospholipid in health and disease.

Keywords:  Crosstalk; Diacyl glycerophospholipid; Hydrocarbon-chain order; Lipid homeostasis; Lipid synthesis enzymes; Lipid−protein interactions; Membrane morphology; Plasmalogen; Plasmalogen deficiency

DOI:  https://doi.org/10.1016/j.plipres.2023.101234
Brain Behav. 2023 May 10. e3054

Impact of sex and serum lipids interaction on working memory: A large-scale brain networks study.

Shujun Zhang, Xuezhen Li, Zhanguo Sun, Yueqin Chen, Yongqiang Yu.

   BACKGROUNDS: Previous studies have demonstrated that both serum lipid levels and sex are crucial factors associated with individual cognition. However, the impact of sex and serum lipid interaction effects on the brain and cognition remains largely unknown. This study aimed to explore the underlying neural mechanisms among sex, serum lipids, and cognition using large-scale brain networks.
METHODS: Resting-state functional MRI data were collected from 157 young healthy adults. Independent component analysis was used to examine large-scale inter- and intra-network functional connectivity (FCs). Peripheral venous blood samples were collected to measure serum lipid levels. The three-back task was employed to assess cognition (i.e., working memory). General linear model, correlation, and mediation analyses were conducted to examine the interaction effects of sex and serum lipids on large-scale brain networks and their relationship with working memory.
RESULTS: We found that inter-network connectivity with the executive control network at its core was more susceptible to sex and triglyceride interaction effects. The intra-network connectivity in the dorsal attention networks (DANs), lateral visual networks, and anterior default mode networks was influenced by the interaction effects of sex and total cholesterol (TC)/low-density lipoprotein cholesterol. Specifically, correlations between serum lipids and affected brain networks were found to be sex-specific. In addition, higher intra-network FC in the right inferior parietal (R-IPL) of the DAN correlated with a longer three-back reaction time in females. More importantly, the relationship between serum TC levels and three-back reaction time was mediated by intra-network connectivity in the R-IPL of the DAN.
CONCLUSIONS: Our findings describe the impact of sex and serum lipid interaction effects on large-scale brain networks, as well as on cognitive function. Our data suggest that sex-specific usage of serum lipids or brain networks would be beneficial for monitoring and therapy in dyslipidemia-related cognition decline.

Keywords:  large-scale brain network; serum lipids; sex; working memory

DOI:  https://doi.org/10.1002/brb3.3054
Metab Brain Dis. 2023 May 06.

Neurometabolic changes in a rat pup model of type C hepatic encephalopathy depend on age at liver disease onset.

Dunja Simicic, Veronika Rackayova, Olivier Braissant, Christian Toso, Graziano Oldani, Dario Sessa, Valérie A McLin, Cristina Cudalbu.

  Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy (1H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to 1H MRS methodological limitations in field strength of clinical magnet.

Keywords:  1H MRS; Bile duct ligation; Chronic liver disease; Neurodevelopment; Type C hepatic encephalopathy

DOI:  https://doi.org/10.1007/s11011-023-01210-w
Nat Commun. 2023 May 09. 14(1): 2674

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

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

DOI: https://doi.org/10.1038/s41467-023-38295-x