bims-medebr 2023-09-17 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–09–17
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Fatty acid binding proteins are novel modulators of synaptic epoxyeicosatrienoic acid signaling in the brain.
Expanding the function of oligodendrocytes to brain energy metabolism.
A tribute to John Edmond: His leadership role in founding the International Conference on Brain Energy Metabolism (ICBEM) meetings and key contributions to substrate metabolism in brain cells.
Altered brain energy metabolism related to astrocytes in Alzheimer's disease.
Understanding the Neuronal Synapse and Challenges Associated with the Mitochondrial Dysfunction in Mild Cognitive Impairment and Alzheimer's Disease.
FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer's disease.
Ketogenic diet alters microglial morphology and changes the hippocampal lipidomic profile distinctively in stress susceptible versus resistant male mice upon repeated social defeat.
Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants.
Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.
Truxillic acid monoamides as fatty acid binding protein 5 inhibitors.
Ketogenic diet changes microglial morphology and the hippocampal lipidomic profile differently in stress susceptible versus resistant male mice upon repeated social defeat.
Rabbit systemic glucose metabolism map by total-body dynamic PET/CT technology.
Microglia contribute to cognitive decline in hypercholesterolemic LDLr-/- mice.
Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.
Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.
Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.
ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.
The Parkinson's disease-associated mutation LRRK2 G2385R alters mitochondrial biogenesis via the PGC-1α-TFAM pathway.
Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic-ischemic encephalopathy.
Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.
Ucp4 Knockdown of Cerebellar Purkinje Cells Induces Bradykinesia.
Effect of PLA2G6 and SMPD1 Variants on the Lipid Metabolism in the Cerebrospinal Fluid of Patients with Parkinson's Disease: A Non-targeted Lipidomics Study.

Sci Rep. 2023 Sep 14. 13(1): 15234

Fatty acid binding proteins are novel modulators of synaptic epoxyeicosatrienoic acid signaling in the brain.

Sherrye T Glaser, Kalani Jayanetti, Saida Oubraim, Andrew Hillowe, Elena Frank, Jason Jong, Liqun Wang, Hehe Wang, Iwao Ojima, Samir Haj-Dahmane, Martin Kaczocha.

Fatty acid binding proteins (FABPs) govern intracellular lipid transport to cytosolic organelles and nuclear receptors. More recently, FABP5 has emerged as a key regulator of synaptic endocannabinoid signaling, suggesting that FABPs may broadly regulate the signaling of neuroactive lipids in the brain. Herein, we demonstrate that brain-expressed FABPs (FABP3, FABP5, and FABP7) interact with epoxyeicosatrienoic acids (EETs) and the peroxisome proliferator-activated receptor gamma agonist 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Among these lipids, EETs displayed highest affinities for FABP3 and FABP5, and 11,12-EET was identified as the preferred FABP ligand. Similarly, 15d-PGJ2 interacted with FABP3 and FABP5 while binding to FABP7 was markedly lower. Molecular modeling revealed unique binding interactions of the ligands within the FABP binding pockets and highlighted major contributions of van der Waals clashes and acyl chain solvent exposure in dictating FABP affinity and specificity. Functional studies demonstrated that endogenous EETs gate the strength of CA1 hippocampal glutamate synapses and that this function was impaired following FABP inhibition. As such, the present study reveals that FABPs control EET-mediated synaptic gating, thereby expanding the functional roles of this protein family in regulating neuronal lipid signaling.

DOI: https://doi.org/10.1038/s41598-023-42504-4
Curr Opin Neurobiol. 2023 Sep 11. pii: S0959-4388(23)00107-1. [Epub ahead of print]83 102782

Expanding the function of oligodendrocytes to brain energy metabolism.

Klaus-Armin Nave, Ebrahim Asadollahi, Andrew Sasmita.

Oligodendrocytes are best known for wrapping myelin, a unique specialization that enables energy-efficient and fast axonal impulse propagation in white matter tracts and fibers of the cortical circuitry. However, myelinating oligodendrocytes have additional metabolic functions that are only gradually understood, including the regulated release of pyruvate/lactate and extracellular vesicles, both of which are in support of the axonal energy balance. The axon-supportive functions of glial cells are older than myelin in nervous system evolution and implicate oligodendrocyte dysfunction and loss of myelin integrity as a risk factor for progressive neurodegeneration in brain diseases.

DOI: https://doi.org/10.1016/j.conb.2023.102782
J Neurochem. 2023 Sep 11.

A tribute to John Edmond: His leadership role in founding the International Conference on Brain Energy Metabolism (ICBEM) meetings and key contributions to substrate metabolism in brain cells.

Mary C McKenna.

  This is a tribute to John Edmond, professor emeritus of biological chemistry in the David Geffen School of Medicine at UCLA, a renowned neurochemist who had a leadership role in founding the ICBEM meeting series in 1993. John was known for his very warm and engaging personality and his innovative approaches to studying the developing brain and auditory system. He was a brilliant scientist and a fun and delightful person. Without John Edmond's enthusiasm and contributions, we would not have the biennial ICBEM meetings which as noted by Dienel et al. "have had a high impact on conceptual and experimental advances" … "in the energetics and metabolism underlying neural functions"… and "on promoting collaborative interactions among neuroscientists." Sadly, John Edmond passed away on February 18, 2022, following a cerebral hemorrhage. He will be greatly missed by his colleagues and friends.

Keywords:  ICBEM meetings; auditory system development; brain development; carbon monoxide; ketones; lipid metabolism

DOI:  https://doi.org/10.1111/jnc.15951
Ann Neurol. 2023 Sep 13.

Altered brain energy metabolism related to astrocytes in Alzheimer's disease.

Kosei Hirata, Kiwamu Matsuoka, Kenji Tagai, Hironobu Endo, Harutsugu Tatebe, Maiko Ono, Naomi Kokubo, Asaka Oyama, Hitoshi Shinotoh, Takahata Keisuke, Takayuki Obata, Masoumeh Dehghani, Jamie Near, Kazunori Kawamura, Ming-Rong Zhang, Hitoshi Shimada, Takanori Yokota, Takahiko Tokuda, Makoto Higuchi, Yuhei Takado.

OBJECTIVE: Increasing evidence suggests that reactive astrocytes are associated with Alzheimer's disease (AD). However, its underlying pathogenesis remains unknown. Given the role of astrocytes in energy metabolism, reactive astrocytes may contribute to altered brain energy metabolism. Astrocytes are primarily considered glycolytic cells, suggesting a preference for lactate production. This study aimed to examine alterations in astrocytic activities and their association with brain lactate levels in AD.
METHODS: The study included 30 AD and 30 cognitively unimpaired (CU) subjects. For AD subjects, amyloid and tau depositions were confirmed by positron emission tomography (PET) using [11 C]PiB and [18 F]florzolotau, respectively. Myo-inositol, an astroglial marker, and lactate in the posterior cingulate cortex (PCC) were quantified by magnetic resonance spectroscopy (MRS). These MRS metabolites were compared with plasma biomarkers, including glial fibrillary acidic protein (GFAP) as another astrocytic marker, and amyloid and tau-PET.
RESULTS: Myo-inositol and lactate levels were higher in AD than in CU (p < 0.05). Myo-inositol levels correlated with lactate levels (r = 0.272, p = 0.047). Myo-inositol and lactate levels were positively associated with the Clinical Dementia Rating sum-of-boxes scores (p < 0.05). Significant correlations were noted between myo-inositol levels and plasma GFAP, tau phosphorylated at threonine 181 levels, and amyloid and tau-PET accumulation in the PCC (p < 0.05).
INTERPRETATION: We found high myo-inositol levels accompanied by increased lactate levels in the PCC in AD, indicating a link between reactive astrocytes and altered brain energy metabolism. Myo-inositol and plasma GFAP may reflect similar astrocytic changes as biomarkers of AD. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26797
Mitochondrion. 2023 Sep 12. pii: S1567-7249(23)00081-8. [Epub ahead of print]

Understanding the Neuronal Synapse and Challenges Associated with the Mitochondrial Dysfunction in Mild Cognitive Impairment and Alzheimer's Disease.

Harkomal Verma, Prabhakar Gangwar, Anuradha Yadav, Bharti Yadav, Rashmi Rao, Sharanjot Kaur, Puneet Kumar, Monisha Dhiman, Giulio Taglialatela, Anil Kumar Mantha.

  Synaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (ψ) gradient exists and is highest in the somal region. Lower ψ in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (Aβ) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD.

Keywords:  Alzheimer's disease; Amyloid beta; DNA base damage; free radicals; hyper-phosphorylated Tau; mitochondria; phytochemicals; synapse

DOI:  https://doi.org/10.1016/j.mito.2023.09.003
Geroscience. 2023 Sep 09.

FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer's disease.

Haylee L Hamilton, Noah A Kinscherf, Garrett Balmer, Mariana Bresque, Shahriar M Salamat, Marcelo R Vargas, Mariana Pehar.

  Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. In partnership with microglial cells, astrocytes are key players in the regulation of neuroinflammation. Fatty acid binding protein 7 (FABP7) belongs to a family of conserved proteins that regulate lipid metabolism, energy homeostasis, and inflammation. FABP7 expression is largely restricted to astrocytes and radial glia-like cells in the adult central nervous system. We observed that treatment of primary hippocampal astrocyte cultures with amyloid β fragment 25-35 (Aβ25-35) induces FABP7 upregulation. In addition, FABP7 expression is upregulated in the brain of APP/PS1 mice, a widely used AD mouse model. Co-immunostaining with specific astrocyte markers revealed increased FABP7 expression in astrocytes. Moreover, astrocytes surrounding amyloid plaques displayed increased FABP7 staining when compared to non-plaque-associated astrocytes. A similar result was obtained in the brain of AD patients. Whole transcriptome RNA sequencing analysis of human astrocytes differentiated from induced pluripotent stem cells (i-astrocytes) overexpressing FABP7 identified 500 transcripts with at least a 2-fold change in expression. Gene Ontology enrichment analysis identified (i) positive regulation of cytokine production and (ii) inflammatory response as the top two statistically significant overrepresented biological processes. We confirmed that wild-type FABP7 overexpression induces an NF-κB-driven inflammatory response in human i-astrocytes. On the other hand, the expression of a ligand-binding impaired mutant FABP7 did not induce NF-κB activation. Together, our results suggest that the upregulation of FABP7 in astrocytes could contribute to the neuroinflammation observed in AD.

Keywords:  Alzheimer’s disease; Amyloid β (Aβ); Astrocytes; Brain lipid binding protein (BLBP); FABP7; Fatty acid binding protein; Inflammation

DOI:  https://doi.org/10.1007/s11357-023-00916-0
bioRxiv. 2023 Aug 29. pii: 2023.08.28.555135. [Epub ahead of print]

Ketogenic diet alters microglial morphology and changes the hippocampal lipidomic profile distinctively in stress susceptible versus resistant male mice upon repeated social defeat.

Fernando González Ibáñez, Torin Halvorson, Kaushik Sharma, Chloe McKee, Micaël Carrier, Katherine Picard, Nathalie Vernoux, Kanchan Bisht, Jessica Deslauriers, Maciej Lalowski, Marie-Ève Tremblay.

Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress.
Highlights: Ketogenic diet tends to promote resistance to psychological stressHippocampal microglia show morphological adaptations to stress and dietMicroglia of stress-susceptible mice make less synaptic contactsMicroglia of ketogenic diet-fed mice show less signs of cellular stressLipids are differentially regulated in the hippocampi of susceptible mice.

DOI: https://doi.org/10.1101/2023.08.28.555135
Hum Mol Genet. 2023 Sep 15. pii: ddad154. [Epub ahead of print]

Systemic proteome phenotypes reveal defective metabolic flexibility in Mecp2 mutants.

Stephanie A Zlatic, Erica Werner, Veda Surapaneni, Chelsea E Lee, Avanti Gokhale, Kaela Singleton, Duc Duong, Amanda Crocker, Karen Gentile, Frank Middleton, Joseph Martin Dalloul, William Li-Yun Liu, Anupam Patgiri, Daniel Tarquinio, Randall Carpenter, Victor Faundez.

  Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.

Keywords:  MECP2; autism; mitochondria; neurodevelopmental disorder; pyruvate

DOI:  https://doi.org/10.1093/hmg/ddad154
Neurobiol Dis. 2023 Sep 12. pii: S0969-9961(23)00308-X. [Epub ahead of print] 106293

Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.

Eric Chai, Zhenyu Chen, Yongchao Mou, Gitika Thakur, Weihai Zhan, Xue-Jun Li.

  Spastic paraplegia type 11 (SPG11) is a common autosomal recessive form of hereditary spastic paraplegia (HSP) characterized by the degeneration of cortical motor neuron axons, leading to muscle spasticity and weakness. Impaired lipid trafficking is an emerging pathology in neurodegenerative diseases including SPG11, though its role in axonal degeneration of human SPG11 neurons remains unknown. Here, we established a pluripotent stem cell-based SPG11 model by knocking down the SPG11 gene in human embryonic stem cells (hESCs). These stem cells were then differentiated into cortical projection neurons (PNs), the cell types affected in HSP patients, to examine axonal defects and cholesterol distributions. Our data revealed that SPG11 deficiency led to reduced axonal outgrowth, impaired axonal transport, and accumulated swellings, recapitulating disease-specific phenotypes. In SPG11-knockdown neurons, cholesterol was accumulated in lysosome and reduced in plasma membrane, revealing impairments in cholesterol trafficking. Strikingly, the liver-X-receptor (LXR) agonists restored cholesterol homeostasis, leading to the rescue of subsequent axonal defects in SPG11-deficient cortical PNs. To further determine the implication of impaired cholesterol homeostasis in SPG11, we examined the cholesterol distribution in cortical PNs generated from SPG11 disease-mutation knock-in hESCs, and observed a similar cholesterol trafficking impairment. Moreover, LXR agonists rescued the aberrant cholesterol distribution and mitigated the degeneration of SPG11 disease-mutated neurons. Taken together, our data demonstrate impaired cholesterol trafficking underlying axonal degeneration of SPG11 human neurons, and highlight the therapeutic potential of LXR agonists for SPG11 through restoring cholesterol homeostasis.

Keywords:  Axonal degeneration; Cholesterol intracellular trafficking; Cortical projection neuron; Hereditary spastic paraplegias; Human pluripotent stem cells; LXR agonist

DOI:  https://doi.org/10.1016/j.nbd.2023.106293
Bioorg Med Chem. 2023 Sep 04. pii: S0968-0896(23)00312-7. [Epub ahead of print]94 117464

Truxillic acid monoamides as fatty acid binding protein 5 inhibitors.

Chuanzhou Zhu, Livia Schutz, Kalani Jayanetti, Kathryn Takemura, Faniya Doswell, Liqun Wang, Iwao Ojima, Martin Kaczocha.

  Fatty acid binding proteins (FABPs) are intracellular chaperones that deliver bioactive lipids to cytosolic enzymes and nuclear receptors, thereby regulating diverse biological functions. FABP5 is a member of the FABP family that mediates endocannabinoid transport and inactivation, with pharmacological or genetic FABP5 inhibition conferring antinociceptive effects. Consequently, FABP5 inhibitors have emerged as promising analgesics and demonstrate antinociceptive activity in models of pain. Recently developed FABP5 inhibitors based upon the α-truxillic acid monoester (TAME) scaffold demonstrate high affinities for FABP5 but are commonly accompanied by reduced selectivity against related FABPs, notably FABP3 that is expressed in the heart, highlighting the need to identify additional scaffolds that afford enhanced selectivity while maintaining FABP5 potency. Here, we describe the synthesis and biological evaluation of truxillic acid monoamides (TAMADs) as potent, selective, and efficacious FABP5 inhibitors. Combining in silico molecular docking and in vitro binding assay approaches, our findings demonstrate that TAMADs exhibit exceptional selectivity against FABP3 and several compounds attain high FABP5 affinities. Examination of antinociceptive activity revealed that TAMADs and their corresponding TAMEs demonstrate comparable efficacy and temporal activity profiles in vivo. These results position TAMAD as a suitable scaffold for the development of FABP5 inhibitors with diminished FABP3 cross-reactivity.

Keywords:  Antinociceptive agent, computer-assisted drug design; Fatty acid binding protein; Inhibitor; Pain; Truxillic acid monoamide; Truxillic acid monoester

DOI:  https://doi.org/10.1016/j.bmc.2023.117464
Brain Behav Immun. 2023 Sep 07. pii: S0889-1591(23)00270-2. [Epub ahead of print]

Ketogenic diet changes microglial morphology and the hippocampal lipidomic profile differently in stress susceptible versus resistant male mice upon repeated social defeat.

Fernando González Ibáñez, Torin Halvorson, Kaushik Sharma, Chloe Grace McKee, Micaël Carrier, Katherine Picard, Nathalie Vernoux, Kanchan Bisht, Jessica Deslauriers, Maciej Lalowski, Marie-Ève Tremblay.

  Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress.

Keywords:  Electron microscopy; Hippocampus; Ketogenic diet; Lipidomics; Microglia; Psychological stress; Repeated social defeat

DOI:  https://doi.org/10.1016/j.bbi.2023.09.006
Nucl Med Commun. 2023 Sep 14.

Rabbit systemic glucose metabolism map by total-body dynamic PET/CT technology.

Haochen Wang, Xue Xie, Yanhua Duan, Leiying Chai, Kun Li, Jianfeng Qiu, Zhaoping Cheng.

BACKGROUND: This study evaluated total-body glucose metabolism in a preclinical lab animal, the rabbit, by employing a dynamic glucose metabolic image obtained with total-body fluorine-18 fluorodeoxyglucose (18F-FDG) PET/computed tomography (PET/CT).
METHODS: The dynamic total-body PET/CT system was used to obtain glucose metabolic imaging from 10 sedated body-matched rabbits. The standard uptake value (SUV) of 18F-FDG was used to evaluate glucose metabolism. In addition, the correlation between glucose metabolism and sexes was assessed, as well as metabolic differences between left- and right sides.
RESULTS: We found significant distribution heterogeneity of glucose in several organs across the entire body. There were no significant metabolic differences between sexes and between bilateral sides in the 10 rabbits. Thereafter, we assayed the major organ SUV changes by dynamic PET/CT of the major organs. The heart, liver, and urinary system showed more 18F-FDG, whereas the skeletal muscle, brain, spinal cord, and lungs incorporated less 18F-FDG. The phenotype of 18F-FDG uptake was highly correlated with the physiological functions. The 18F-FDG accumulation in urinary system were observed which could reflect the renal parenchyma glucose metabolism indirectly. However, the low 18F-FDG uptake in the brain and spinal cord was due to sedation.
CONCLUSION: The total-body glucose metabolic atlas depicted with 18F-FDG dynamic PET/CT may be used as a reference for assessing pathological 18F-FDG uptake. Furthermore, this study could be a reference for preclinical research involving abnormality of glucose metabolism.

DOI: https://doi.org/10.1097/MNM.0000000000001767
J Neurochem. 2023 Sep 11.

Microglia contribute to cognitive decline in hypercholesterolemic LDLr-/- mice.

Matheus Scarpatto Rodrigues, Natalia Baltazar do Nascimento, Hemelin Resende Farias, Taina Schons, Alessandra Gonçalves Machado, Eduarda Behenck, Ariadni Mesquita, Rachel Krolow Bast, Josiani Budni, David Engblom, Andreza Fabro de Bem, Jade de Oliveira.

  Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr-/- ) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr-/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr-/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr-/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr-/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr-/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr-/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr-/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.

Keywords:  LDLr−/− mice; familial hypercholesterolemia; memory; microglial cell morphology; perivascular microglia

DOI:  https://doi.org/10.1111/jnc.15952
J Transl Med. 2023 09 09. 21(1): 613

Mitochondrial dysfunction in neurodegenerative disorders: Potential therapeutic application of mitochondrial transfer to central nervous system-residing cells.

Felipe A Bustamante-Barrientos, Noymar Luque-Campos, María Jesús Araya, Eliana Lara-Barba, Javiera de Solminihac, Carolina Pradenas, Luis Molina, Yeimi Herrera-Luna, Yildy Utreras-Mendoza, Roberto Elizondo-Vega, Ana María Vega-Letter, Patricia Luz-Crawford.

Mitochondrial dysfunction is reiteratively involved in the pathogenesis of diverse neurodegenerative diseases. Current in vitro and in vivo approaches support that mitochondrial dysfunction is branded by several molecular and cellular defects, whose impact at different levels including the calcium and iron homeostasis, energetic balance and/or oxidative stress, makes it difficult to resolve them collectively given their multifactorial nature. Mitochondrial transfer offers an overall solution since it contains the replacement of damage mitochondria by healthy units. Therefore, this review provides an introducing view on the structure and energy-related functions of mitochondria as well as their dynamics. In turn, we summarize current knowledge on how these features are deregulated in different neurodegenerative diseases, including frontotemporal dementia, multiple sclerosis, amyotrophic lateral sclerosis, Friedreich ataxia, Alzheimer´s disease, Parkinson´s disease, and Huntington's disease. Finally, we analyzed current advances in mitochondrial transfer between diverse cell types that actively participate in neurodegenerative processes, and how they might be projected toward developing novel therapeutic strategies.

DOI: https://doi.org/10.1186/s12967-023-04493-w
Front Nutr. 2023 ;10 1227431

Exploring the impact of ketogenic diet on multiple sclerosis: obesity, anxiety, depression, and the glutamate system.

Jose Enrique de la Rubia Ortí, María Cuerda-Ballester, Claudia Emmanuela Sanchis-Sanchis, Jose María Lajara Romance, Esther Navarro-Illana, María Pilar García Pardo.

   Background: Multiple sclerosis (MS) is a neurodegenerative disorder. Individuals with MS frequently present symptoms such as functional disability, obesity, and anxiety and depression. Axonal demyelination can be observed and implies alterations in mitochondrial activity and increased inflammation associated with disruptions in glutamate neurotransmitter activity. In this context, the ketogenic diet (KD), which promotes the production of ketone bodies in the blood [mainly β-hydroxybutyrate (βHB)], is a non-pharmacological therapeutic alternative that has shown promising results in peripheral obesity reduction and central inflammation reduction. However, the association of this type of diet with emotional symptoms through the modulation of glutamate activity in MS individuals remains unknown.
Aim: To provide an update on the topic and discuss the potential impact of KD on anxiety and depression through the modulation of glutamate activity in subjects with MS.
Discussion: The main findings suggest that the KD, as a source of ketone bodies in the blood, improves glutamate activity by reducing obesity, which is associated with insulin resistance and dyslipidemia, promoting central inflammation (particularly through an increase in interleukins IL-1β, IL-6, and IL-17). This improvement would imply a decrease in extrasynaptic glutamate activity, which has been linked to functional disability and the presence of emotional disorders such as anxiety and depression.

Keywords:  anxiety; depression; glutamate; ketogenic diets; multiple sclerosis; obesity

DOI:  https://doi.org/10.3389/fnut.2023.1227431
Cell Biosci. 2023 Sep 13. 13(1): 171

Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.

Vladimir Rudajev, Jiri Novotny.

  Amyloid β is considered a key player in the development and progression of Alzheimer's disease (AD). Many studies investigating the effect of statins on lowering cholesterol suggest that there may be a link between cholesterol levels and AD pathology. Since cholesterol is one of the most abundant lipid molecules, especially in brain tissue, it affects most membrane-related processes, including the formation of the most dangerous form of amyloid β, Aβ42. The entire Aβ production system, which includes the amyloid precursor protein (APP), β-secretase, and the complex of γ-secretase, is highly dependent on membrane cholesterol content. Moreover, cholesterol can affect amyloidogenesis in many ways. Cholesterol influences the stability and activity of secretases, but also dictates their partitioning into specific cellular compartments and cholesterol-enriched lipid rafts, where the amyloidogenic machinery is predominantly localized. The most complicated relationships have been found in the interaction between cholesterol and APP, where cholesterol affects not only APP localization but also the precise character of APP dimerization and APP processing by γ-secretase, which is important for the production of Aβ of different lengths. In this review, we describe the intricate web of interdependence between cellular cholesterol levels, cholesterol membrane distribution, and cholesterol-dependent production of Aβ, the major player in AD.

Keywords:  Amyloid precursor protein; Amyloid β; Amyloidogenesis; Cholesterol; Secretase

DOI:  https://doi.org/10.1186/s13578-023-01127-y
Diabetologia. 2023 Sep 15.

ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis.

Kavaljit H Chhabra, Siresha Bathina, Tumininu S Faniyan, Dennis J Samuel, Muhammad Ummear Raza, Leticia Maria de Souza Cordeiro, Gonzalo Viana Di Prisco, Brady K Atwood, Jorge Robles, Lauren Bainbridge, Autumn Davis.

   AIMS/HYPOTHESIS: The brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus.
METHODS: Here we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology.
RESULTS: Adgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis.
CONCLUSIONS/INTERPRETATION: Altogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.

Keywords:  Diabetes; Glucose receptor; Glucose sensing; Hypothalamus; Mouse models; Obesity

DOI:  https://doi.org/10.1007/s00125-023-06010-6
Mitochondrion. 2023 Sep 12. pii: S1567-7249(23)00082-X. [Epub ahead of print]

The Parkinson's disease-associated mutation LRRK2 G2385R alters mitochondrial biogenesis via the PGC-1α-TFAM pathway.

Jian Xue, Jinbao Zhang, Jinru Zhang, Junyi Liu, Fen Wang, Kai Li, Chunfeng Liu.

  Mutations in the Leucine-rich repeat protein kinase 2 (LRRK2) gene are the most frequent cause of familial Parkinson's disease (PD). Although LRRK2 has been extensively studied, the pathogenic mechanism of the LRRK2 G2385R mutation, which is most common in Asian populations, especially in the Chinese Han population, remains unclear. In this study, we demonstrated that the LRRK2 G2385R mutation in HEK293T cells led to a reduction in cellular PGC-1α protein expression and inhibition of mitochondrial biogenesis through the PGC-1α-TFAM pathway. This resulted in a decrease in mitochondrial genome expression, which in turn impaired the normal electron transfer process of the oxidative phosphorylation respiratory chain, leading to mitochondrial dysfunction and onset of apoptosis. The mitochondrial dysfunction and apoptosis caused by the LRRK2 G2385R mutation were significantly alleviated by antioxidant Idebenone, which provides a theoretical basis for the subsequent development of precise treatment specifically for PD patients with LRRK2 G2385R mutation. Further validation of our findings in neurons and animal models are necessary.

Keywords:  Idebenone; LRRK2 G2385R; Mitochondrial biogenesis; Mitochondrial dysfunction; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.mito.2023.09.002
Front Neurol. 2023 ;14 1231743

Long-chain omega-3 polyunsaturated fatty acids are reduced in neonates with substantial brain injury undergoing therapeutic hypothermia after hypoxic-ischemic encephalopathy.

Simon C Dyall, Isabell Nessel, Jennine A Sharpe, Ping K Yip, Adina T Michael-Titus, Divyen K Shah.

  Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good (n = 10), or poor outcomes (n = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE.

Keywords:  DHA; EPA; Omega-3 Index; hypoxic–ischemic encephalopathy; lipid peroxidation; mild therapeutic hypothermia; newborns; omega-3 polyunsaturated fatty acids

DOI:  https://doi.org/10.3389/fneur.2023.1231743
Cold Spring Harb Mol Case Stud. 2023 Sep 14. pii: mcs.a006295. [Epub ahead of print]

Novel pathogenic UQCRC2 variants in a female with normal neurodevelopment.

Lea Abou Haidar, Robert Charles Harris, Panayotis Pachnis, Hongli Chen, Garrett K Gotway, Min Ni, Ralph J DeBerardinis.

  Electron transport chain (ETC) disorders are a group of rare, multisystem diseases caused by impaired oxidative phosphorylation and energy production. Deficiencies in complex III (CIII), also known as ubiquinol-cytochrome c reductase, are particularly rare in humans. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) encodes a subunit of CIII that plays a crucial role in dimerization. Several pathogenic UQCRC2 variants have been identified in patients presenting with metabolic abnormalities that include lactic acidosis, hyperammonemia, hypoglycemia, and organic aciduria. Almost all previously-reported UQCRC2-deficient patients exhibited neurodevelopmental involvement, including developmental delays and structural brain anomalies. Here we describe a girl who presented at 3 years of age with lactic acidosis, hyperammonemia, and hypoglycemia, but has not shown any evidence of neurodevelopmental dysfunction by age 15. Whole exome sequencing revealed compound heterozygosity for two novel variants in UQCRC2: c.1189G>A; p.Gly397Arg and c.437T>C; p.Phe146Ser. Here, we discuss the patient's clinical presentation and the likely pathogenicity of these two missense variants.

Keywords:  Acute hyperammonemia; Decreased activity of mitochondrial complex III; Fasting hypoglycemia; Stress/infection-induced lactic acidosis

DOI:  https://doi.org/10.1101/mcs.a006295
Mol Neurobiol. 2023 Sep 09.

Ucp4 Knockdown of Cerebellar Purkinje Cells Induces Bradykinesia.

Ya-Yun Wang, Hui Liu, Shu-Jiao Li, Ban Feng, Yun-Qiang Huang, Shui-Bing Liu, Yan-Ling Yang.

  Although uncoupling protein 4 (UCP4) is the most abundant protein reported in the brain, the biological function of UCP4 in cerebellum and pathological outcome of UCP4 deficiency in cerebellum remain obscure. To evaluate the role of Ucp4 in the cerebellar Purkinje cells (PCs), we generated the conditional knockdown of Ucp4 in PCs (Pcp2cre;Ucp4fl/fl mice) by breeding Ucp4fl/fl mice with Pcp2cre mice. Series results by Western blot, immunofluorescent staining, and triple RNAscope in situ hybridization confirmed the specific ablation of Ucp4 in PCs in Pcp2cre;Ucp4fl/fl mice, but did not affect the expression of Ucp2, the analog of Ucp4. Combined behavioral tests showed that Pcp2cre;Ucp4fl/fl mice displayed a characteristic bradykinesia in the spontaneous movements. The electromyogram recordings detection excluded the possibility of hypotonia in Pcp2cre;Ucp4fl/fl mice. And the electrical patch clamp recordings showed the altered properties of PCs in Pcp2cre;Ucp4fl/fl mice. Moreover, transmission electron microscope (TEM) results showed the increased mitochondrial circularity in PCs; ROS probe imaging showed the increased ROS generation in molecular layer; and finally, microplate reader assay showed the significant changes of mitochondrial functions, including ROS, ATP, and MMP in the isolated cerebellum tissue. The results suggested that the specific knockdown of mitochondrial protein Ucp4 could damage PCs possibly by attacking their mitochondrial function. The present study is the first to report a close relationship between UCP4 deletion with PCs impairment, and suggests the importance of UCP4 in the substantial support of mitochondrial function homeostasis in bradykinesia. UCP4 might be a therapeutic target for the cerebellar-related movement disorder.

Keywords:  Bradykinesia; Cerebellum; Mitochondrial uncoupling protein 4; Movement disorders; Purkinje cells

DOI:  https://doi.org/10.1007/s12035-023-03607-1
Neurol Ther. 2023 Sep 14.

Effect of PLA2G6 and SMPD1 Variants on the Lipid Metabolism in the Cerebrospinal Fluid of Patients with Parkinson's Disease: A Non-targeted Lipidomics Study.

Yongang Li, GuiKai Ji, Mengjia Lian, Xuan Liu, Ying Xu, Yaxing Gui.

   INTRODUCTION: Sleep patterns are more frequently interrupted in patients with Parkinson's disease (PD), and it is still unclear whether genetic factors are involved in PD-related sleep disorders. In this study, we hypothesize that PD-associated genetic risk affects lipid metabolism, which in turn contributes to different types of sleep disorders.
METHODS: We used a non-targeted lipidomics to explore the lipid composition of cerebrospinal fluid (CSF) exosomes derived from patients with PD carrying phospholipase A2 Group VI (PLA2G6) and sphingomyelin phosphodiesterase 1 (SMPD1) mutations.
RESULTS: PLA2G6 mutations (c.1966C > G, Leu656Val; c.2077C > G, Leu693Val; c.1791delC, His597fx69) significantly increase the exosomal content of glycerophospholipids and lysophospholipids, specifically phosphatidylcholine (PC) and lysophosphatidylcholine (LPC). Exosome surface presence of melatomin receptor 1A (MTNR1A) was detectable only in patients with PLA2G6 mutations. We have further shown that, in patients with PD carrying PLA2G6 mutations, sleep latency was significantly longer compared to those carrying WT PLA2G6, and we speculate that functional PLA2G6 mutations lead to structural changes and lipid deregulation of exosomes, which in turn alters exosomal cargo and affects PD-related sleep disorders. In SMPD1, G508R variant-carrying patients with PD abundance of sphingomyelins was significantly higher and had significantly shorter rapid eye movement sleep.
CONCLUSIONS: Our study demonstrated that the disturbed composition and function of CSF-derived exosome lipidome during the pathological stage of PD may affect different types of sleep disorder in PD.

Keywords:  Exosomes; Lipids; PLA2G6; Parkinson's disease; SMPD1

DOI:  https://doi.org/10.1007/s40120-023-00542-0