bims-medebr 2023-01-01 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–01–01
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

Age-associated alterations of brain mitochondria energetics.
UCP2-dependent redox sensing in POMC neurons regulates feeding.
Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.
Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen-glucose deprivation conditions.
Organization of neurochemical interactions in young and older brains as revealed with a network approach: Evidence from proton magnetic resonance spectroscopy (1H-MRS).
Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.
Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.
Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.
Astrocytic Glutamate Transporters and Migraine.
Sex differences in hippocampal structural plasticity and glycosaminoglycan disaccharide levels after neonatal handling.
Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease.
Mitochondrial quality control in the brain: The physiological and pathological roles.
ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons.
Neurometabolic correlates of posturography in normal aging and older adults with mild cognitive impairment: Evidence from a 1H-MRS study.
Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline.
Apolipoprotein E4 inhibits γ-secretase activity via binding to the γ-secretase complex.
Molecular and spatial signatures of mouse brain aging at single-cell resolution.
Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes.
High fat diet exacerbates long-term metabolic, neuropathological, and behavioral derangements in an experimental mouse model of traumatic brain injury.
Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.
Tandem Mass Spectrometry Imaging Enables High Definition for Mapping Lipids in Tissues.

Biochem Biophys Res Commun. 2022 Dec 23. pii: S0006-291X(22)01741-7. [Epub ahead of print]643 1-7

Age-associated alterations of brain mitochondria energetics.

Timur Gainutdinov, Zemfira Gizatullina, Grazyna Debska-Vielhaber, Stefan Vielhaber, Robert Feldmann, Zulfiya Orynbayeva, Frank Norbert Gellerich.

  The study aimed to explore the role of age-associated elevated cytosolic Ca2+ in changes of brain mitochondria energetic processes. Two groups of rats, young adults (4 months) and advanced old (24 months), were evaluated for potential alterations of mitochondrial parameters, the oxidative phosphorylation (OxPhos), membrane potential, calcium retention capacity, activity of glutamate/aspartate carrier (aralar), and ROS formation. We demonstrated that the brain mitochondria of older animals have a lower resistance to Ca2+ stress with resulting consequences. The suppressed complex I OxPhos and decreased membrane potential were accompanied by reduction of the Ca2+ threshold required for induction of mPTP. The Ca2+ binding sites of mitochondrial aralar mediated a lower activity of old brain mitochondria. The altered interaction between aralar and mPTP may underlie mitochondrial dysregulation leading to energetic depression during aging. At the advanced stages of aging, the declined metabolism is accompanied by the diminished oxidative background.

Keywords:  Aging; Aralar; Brain mitochondria; Ca(2+); OxPhos; ROS

DOI:  https://doi.org/10.1016/j.bbrc.2022.12.070
Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01793-4. [Epub ahead of print]41(13): 111894

UCP2-dependent redox sensing in POMC neurons regulates feeding.

Nal Ae Yoon, Sungho Jin, Jung Dae Kim, Zhong Wu Liu, Qiushi Sun, Rebecca Cardone, Richard Kibbey, Sabrina Diano.

  Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2PomcKO), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2PomcKO mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism.

Keywords:  CP: Metabolism; CP: Neuroscience; NADH; UCP2; feeding behavior; glucose; hypothalamus; lactate; lipid utilization; mitochondria; pro-opiomelanocortin neurons; redox signaling

DOI:  https://doi.org/10.1016/j.celrep.2022.111894
Neurobiol Aging. 2022 Dec 05. pii: S0197-4580(22)00245-7. [Epub ahead of print]

Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice.

Rebecca M Fleeman, Amanda M Snyder, Madison K Kuhn, Dennis C Chan, Grace C Smith, Nicole A Crowley, Amy C Arnold, Elizabeth A Proctor.

  The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures are APOE genotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.

Keywords:  APOE; Alzheimer's disease; Cytokines; Inflammation; Metabolism

DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.11.015
J Neuroinflammation. 2022 Dec 26. 19(1): 314

Lactate attenuates astrocytic inflammation by inhibiting ubiquitination and degradation of NDRG2 under oxygen-glucose deprivation conditions.

Jinying Xu, Tong Ji, Guichen Li, Haiying Zhang, Yangyang Zheng, Meiying Li, Jie Ma, Yulin Li, Guangfan Chi.

   BACKGROUND: Brain lactate concentrations are enhanced in response to cerebral ischemia and promote the formation of reactive astrocytes, which are major components of the neuroinflammatory response and functional recovery, following cerebral ischemia. NDRG2 is upregulated during reactive astrocyte formation. However, its regulation and function are unclear. We studied the relationship between lactate and NDRG2 in astrocytes under conditions of ischemia or oxygen-glucose deprivation (OGD).
METHODS: We examined astrocytic NDRG2 expression after middle cerebral artery occlusion (MCAO) using western blot and immunofluorescence staining. Under hypoxia conditions, we added exogenous L-lactate sodium (lactate) to cultured primary astrocytes to explore the effects of lactate on the ubiquitination modification of NDRG2. We profiled the transcriptomic features of NDRG2 silencing in astrocytes after 8 h of OGD conditions as well as exogenous lactate treatment by performing RNA-seq. Finally, we evaluated the molecular mechanisms of NDRG2 in regulating TNFα under OGD conditions using western blot and immunohistochemistry.
RESULTS: Reactive astrocytes strongly expressed NDRG2 in a rat model of MCAO. We also showed that lactate stabilizes astrocytic NDRG2 by inhibiting its ubiquitination. NDRG2 inhibition in astrocytes increased inflammation and upregulated immune-associated genes and signaling pathways. NDRG2 knockdown induced TNFα expression and secretion via c-Jun phosphorylation.
CONCLUSIONS: We revealed that under OGD conditions, lactate plays an important anti-inflammatory role and inhibits TNFα expression by stabilizing NDRG2, which is beneficial for neurological functional recovery. NDRG2 may be a new therapeutic target for cerebral ischemia.

Keywords:  Astrocyte; Cerebral ischemia; Inflammation; Lactate; NDRG2; Oxygen–glucose deprivation

DOI:  https://doi.org/10.1186/s12974-022-02678-6
Neuroimage. 2022 Dec 22. pii: S1053-8119(22)00951-X. [Epub ahead of print]266 119830

Organization of neurochemical interactions in young and older brains as revealed with a network approach: Evidence from proton magnetic resonance spectroscopy (1H-MRS).

Geraldine Rodríguez-Nieto, Oron Levin, Lize Hermans, Akila Weerasekera, Anca Croitor Sava, Astrid Haghebaert, Astrid Huybrechts, Koen Cuypers, Dante Mantini, Uwe Himmelreich, Stephan P Swinnen.

  Aging is associated with alterations in the brain including structural and metabolic changes. Previous research has focused on neurometabolite level differences associated to age in a variety of brain regions, but the relationship among metabolites across the brain has been much less studied. Investigating these relationships can reveal underlying neurometabolic processes, their interdependency, and their progress throughout the lifespan. Using 1H-MRS, we investigated the relationship among metabolite concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-Inositol (mIns) and glutamate-glutamine complex (Glx) in seven voxel locations, i.e., bilateral sensorimotor cortex, bilateral striatum, pre-supplementary motor area, right inferior frontal gyrus and occipital cortex. These measurements were performed on 59 human participants divided in two age groups: young adults (YA: 23.2 ± 4.3; 18-34 years) and older adults (OA: 67.5 ± 3.9; 61-74 years). Our results showed age-related differences in NAA, Cho, and mIns across brain regions, suggesting the presence of neurodegeneration and altered gliosis. Moreover, associative patterns among NAA, Cho and Cr were observed across the selected brain regions, which differed between young and older adults. Whereas most of metabolite concentrations were inhomogeneous across different brain regions, Cho levels were shown to be strongly related across brain regions in both age groups. Finally, we found metabolic associations between homologous brain regions (SM1 and striatum) in the OA group, with NAA showing a significant correlation between bilateral sensorimotor cortices (SM1) and mIns levels being correlated between the bilateral striata. We posit that a network perspective provides important insights regarding the potential interactions among neurochemicals underlying metabolic processes at a local and global level and their relationship with aging.

Keywords:  Aging; Choline; Graph theory; Magnetic resonance spectroscopy; Metabolites; Networks

DOI:  https://doi.org/10.1016/j.neuroimage.2022.119830
Cell Mol Neurobiol. 2022 Dec 26.

Alzheimer's-Associated Upregulation of Mitochondria-Associated ER Membranes After Traumatic Brain Injury.

Rishi R Agrawal, Delfina Larrea, Yimeng Xu, Lingyan Shi, Hylde Zirpoli, Leslie G Cummins, Valentina Emmanuele, Donghui Song, Taekyung D Yun, Frank P Macaluso, Wei Min, Steven G Kernie, Richard J Deckelbaum, Estela Area-Gomez.

  Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD.

Keywords:  Alzheimer’s; Brain injury; Contact sites; Lipids; Mitochondria; Neurodegeneration

DOI:  https://doi.org/10.1007/s10571-022-01299-0
Life Sci. 2022 Dec 26. pii: S0024-3205(22)01025-6. [Epub ahead of print] 121325

Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases.

Hasan Turkez, Ozlem Altay, Serkan Yildirim, Xiangyu Li, Hong Yang, Cemil Bayram, Ismail Bolat, Sena Oner, Ozlem Ozdemir Tozlu, Mehmet Enes Arslan, Muhammad Arif, Burak Yulug, Lutfu Hanoglu, Seyda Cankaya, Simon Lam, Halil Aziz Velioglu, Ebru Coskun, Ezgi Idil, Rahim Nogaylar, Ahmet Ozsimsek, Ahmet Hacimuftuoglu, Saeed Shoaie, Cheng Zhang, Jens Nielsen, Jan Borén, Mathias Uhlén, Adil Mardinoglu.

   BACKGROUND: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism.
METHODS: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation.
FINDINGS: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats.
INTERPRETATION: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.

Keywords:  Animal model; Combined metabolic activators; Genome-scale metabolic model; Neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.lfs.2022.121325
Transl Neurodegener. 2022 Dec 28. 11(1): 58

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer's disease protects against mitochondrial dysfunction and mitigates brain pathology.

Ankit Verma, Anna Shteinfer-Kuzmine, Nikita Kamenetsky, Srinivas Pittala, Avijit Paul, Edna Nahon Crystal, Alberto Ouro, Vered Chalifa-Caspi, Swaroop Kumar Pandey, Alon Monsengo, Noga Vardi, Shira Knafo, Varda Shoshan-Barmatz.

   BACKGROUND: Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.
METHODS: To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests.
RESULTS: In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load.
CONCLUSIONS: The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.

Keywords:  Alzheimer’s disease; Metabolism; Mitochondria; Neuroinflammation; VDAC1

DOI:  https://doi.org/10.1186/s40035-022-00329-7
Neurochem Res. 2022 Dec 30.

Astrocytic Glutamate Transporters and Migraine.

Fiorenzo Conti, Daniela Pietrobon.

  Glutamate levels and lifetime in the brain extracellular space are dinamically regulated by a family of Na+- and K+-dependent glutamate transporters, which thereby control numerous brain functions and play a role in numerous neurological and psychiatric diseases. Migraine is a neurological disorder characterized by recurrent attacks of typically throbbing and unilateral headache and by a global dysfunction in multisensory processing. Familial hemiplegic migraine type 2 (FHM2) is a rare monogenic form of migraine with aura caused by loss-of-function mutations in the α2 Na/K ATPase (α2NKA). In the adult brain, this pump is expressed almost exclusively in astrocytes where it is colocalized with glutamate transporters. Knockin mouse models of FHM2 (FHM2 mice) show a reduced density of glutamate transporters in perisynaptic astrocytic processes (mirroring the reduced expression of α2NKA) and a reduced rate of glutamate clearance at cortical synapses during neuronal activity and sensory stimulation. Here we review the migraine-relevant alterations produced by the astrocytic glutamate transport dysfunction in FHM2 mice and their underlying mechanisms, in particular regarding the enhanced brain susceptibility to cortical spreading depression (the phenomenon that underlies migraine aura and can also initiate the headache mechanisms) and the enhanced algesic response to a migraine trigger.

Keywords:  Astrocytes; Glutamate transporters: GLT-1; Migraine; Na/K pump; Pain; Spreading depolarization

DOI:  https://doi.org/10.1007/s11064-022-03849-w
Exp Neurol. 2022 Dec 24. pii: S0014-4886(22)00338-7. [Epub ahead of print]361 114313

Sex differences in hippocampal structural plasticity and glycosaminoglycan disaccharide levels after neonatal handling.

Joel G Hashimoto, Mo L Singer, Calla M Goeke, Fuming Zhang, Yuefan Song, Ke Xia, Robert J Linhardt, Marina Guizzetti.

  In this study we investigated the effects of a neonatal handling protocol that mimics the handling of sham control pups in protocols of neonatal exposure to brain insults on dendritic arborization and glycosaminoglycan (GAG) levels in the developing brain. GAGs are long, unbranched polysaccharides, consisting of repeating disaccharide units that can be modified by sulfation at specific sites and are involved in modulating neuronal plasticity during brain development. In this study, male and female Sprague-Dawley rats underwent neonatal handling daily between post-natal day (PD)4 and PD9, with brains analyzed on PD9. Neuronal morphology and morphometric analysis of the apical and basal dendritic trees of CA1 hippocampal pyramidal neurons were carried out by Golgi-Cox staining followed by neuron tracing and analysis with the software Neurolucida. Chondroitin sulfate (CS)-, Hyaluronic Acid (HA)-, and Heparan Sulfate (HS)-GAG disaccharide levels were quantified in the hippocampus by Liquid Chromatography/Mass Spectrometry analyses. We found sex by neonatal handling interactions on several parameters of CA1 pyramidal neuron morphology and in the levels of HS-GAGs, with females, but not males, showing an increase in both dendritic arborization and HS-GAG levels. We also observed increased expression of glucocorticoid receptor gene Nr3c1 in the hippocampus of both males and females following neonatal handling suggesting that both sexes experienced a similar stress during the handling procedure. This is the first study to show sex differences in two parameters of brain plasticity, CA1 neuron morphology and HS-GAG levels, following handling stress in neonatal rats.

Keywords:  Dendritic arborization; Glycosaminoglycans (GAGs); Neonatal handling; Sex differences

DOI:  https://doi.org/10.1016/j.expneurol.2022.114313
Prog Neurobiol. 2022 Dec 26. pii: S0301-0082(22)00186-1. [Epub ahead of print] 102400

Brain regions show different metabolic and protein arginine methylation phenotypes in frontotemporal dementias and Alzheimer's disease.

Fangrong Zhang, Anastasia Rakhimbekova, Tammaryn Lashley, Tobias Madl.

  Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disease with multiple histopathological subtypes. FTD patients share similar symptoms with Alzheimer's disease (AD). Hence, FTD patients are commonly misdiagnosed as AD, despite the consensus clinical diagnostic criteria. It is therefore of great clinical need to identify a biomarker that can distinguish FTD from AD and control individuals, and potentially further differentiate between FTD pathological subtypes. We conducted a metabolomic analysis on post-mortem human brain tissue from three regions: cerebellum, frontal cortex and occipital cortex from control, FTLD-TDP type A, type A-C9, type C and AD. Our results indicate that the brain subdivisions responsible for different functions show different metabolic patterns. We further explored the region-specific metabolic characteristics of different FTD subtypes and AD patients. Different FTD subtypes and AD share similar metabolic phenotypes in the cerebellum, but AD exhibited distinct metabolic patterns in the frontal and occipital regions compared to FTD. The identified brain region-specific metabolite biomarkers could provide a tool for distinguishing different FTD subtypes and AD and provide the first insights into the metabolic changes of FTLD-TDP type A, type A-C9, type C and AD in different regions of the brain. The importance of protein arginine methylation in neurodegenerative disease has come to light, so we investigated whether the arginine methylation level contributes to disease pathogenesis. Our findings provide new insights into the relationship between arginine methylation and metabolic changes in FTD subtypes and AD that could be further explored, to study the molecular mechanism of pathogenesis.

Keywords:  Alzheimer’s disease; frontotemporal dementia; metabolism; protein arginine methylation; region-specific

DOI:  https://doi.org/10.1016/j.pneurobio.2022.102400
Front Neurosci. 2022 ;16 1075141

Mitochondrial quality control in the brain: The physiological and pathological roles.

Xurui Shen, Peixin Sun, Hao Zhang, Hanting Yang.

  The human brain has high energetic expenses and consumes over 20% of total oxygen metabolism. Abnormal brain energy homeostasis leads to various brain diseases. Among multiple factors that contribute to these diseases, mitochondrial dysfunction is one of the most common causes. Maintenance of mitochondrial integrity and functionality is of pivotal importance to brain energy generation. Mitochondrial quality control (MQC), employing the coordination of multiple mechanisms, is evolved to overcome many mitochondrial defects. Thus, not surprisingly, aberrant mitochondrial quality control results in a wide range of brain disorders. Targeting MQC to preserve and restore mitochondrial function has emerged as a promising therapeutic strategy for the prevention and treatment of brain diseases. Here, we set out to summarize the current understanding of mitochondrial quality control in brain homeostasis. We also evaluate potential pharmaceutically and clinically relevant targets in MQC-associated brain disorders.

Keywords:  brain disorders; mitochondrial dysfunction; mitochondrial homeostasis; mitochondrial quality control; therapeutic target

DOI:  https://doi.org/10.3389/fnins.2022.1075141
Free Radic Biol Med. 2022 Dec 26. pii: S0891-5849(22)01112-1. [Epub ahead of print]

ACSL4 and the lipoxygenases 15/15B are pivotal for ferroptosis induced by iron and PUFA dyshomeostasis in dopaminergic neurons.

Hind Bouchaoui, Laura Mahoney-Sanchez, Guillaume Garçon, Olivier Berdeaux, Laurent Y Alleman, David Devos, James A Duce, Jean-Christophe Devedjian.

  Ferroptosis, an iron-dependent regulated cell death triggered by high lipid peroxide levels, has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD). Brain regions such as the striatum are highly rich in both peroxidation susceptible PUFAs and iron, which accumulate at a greater rate than age in PD. The exact molecular pathways and patho-physiological conditions promoting cell death in the dopaminergic neurons that are particularly susceptible in PD remain elusive. In the current work, we show that modifying the PUFA composition in membranes of dopaminergic neurons using arachidonic acid (AA) can determine ferroptosis susceptibility. Furthermore, cotreatment with iron (Fe), increases AA-containing phospholipid association and synergistically promotes high lipid peroxidation to facilitate ferroptosis. Ex vivo analysis with organotypic brain slices, confirm that AA + Fe induces cell death in the nigrostriatal pathway and can be rescued by the anti-ferroptotic drug Ferrostatin-1. Prevention of ferroptotic AA + Fe induced cell death through inhibition of ACSL4, ALOX15 or ALOX15B provides mechanistic support of this lipid peroxidation pathway being involved in dopaminergic neuronal death and novel potential pharmacological targets for neuroprotective strategies in PD.

Keywords:  Arachidonic acid; Dopaminergic neurons; Ferroptosis; Iron; Lipid peroxidation; Parkinson's disease

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.086
Neuroimage Clin. 2022 Dec 24. pii: S2213-1582(22)00369-2. [Epub ahead of print]37 103304

Neurometabolic correlates of posturography in normal aging and older adults with mild cognitive impairment: Evidence from a 1H-MRS study.

Oron Levin, Wouter A J Vints, Gal Ziv, Gintarė Katkutė, Simona Kušleikienė, Kristina Valatkevičienė, Samrat Sheoran, Margarita Drozdova-Statkevičienė, Rymantė Gleiznienė, Mati Pääsuke, Vilma Dudonienė, Uwe Himmelreich, Vida J Česnaitienė, Nerijus Masiulis.

  Proton magnetic resonance spectroscopy (1H-MRS) holds promise for revealing and understanding neurodegenerative processes associated with cognitive and functional impairments in aging. In the present study, we examined the neurometabolic correlates of balance performance in 42 cognitively intact older adults (healthy controls - HC) and 26 older individuals that were diagnosed with mild cognitive impairment (MCI). Neurometabolite ratios of total N-acetyl aspartate (tNAA), glutamate-glutamine complex (Glx), total choline (tCho) and myo-inositol (mIns) relative to total creatine (tCr) were assessed using single voxel 1H-MRS in four different brain regions. Regions of interest were the left hippocampus (HPC), dorsal posterior cingulate cortex (dPCC), left sensorimotor cortex (SM1), and right dorsolateral prefrontal cortex (dlPFC). Center-of-pressure velocity (Vcop) and dual task effect (DTE) were used as measures of balance performance. Results indicated no significant group differences in neurometabolite ratios and balance performance measures. However, our observations revealed that higher tCho/tCr and mIns/tCr in hippocampus and dPCC were generic predictors of worse balance performance, suggesting that neuroinflammatory processes in these regions might be a driving factor for impaired balance performance in aging. Further, we found that higher tNAA/tCr and mIns/tCr and lower Glx/tCr in left SM1 were predictors of better balance performance in MCI but not in HC. The latter observation hints at the possibility that individuals with MCI may upregulate balance control through recruitment of sensorimotor pathways.

Keywords:  Aging; Balance control; Brain neurometabolites; Dual-task effect; Postural stability

DOI:  https://doi.org/10.1016/j.nicl.2022.103304
J Adv Res. 2023 Jan;pii: S2090-1232(22)00054-6. [Epub ahead of print]43 233-245

Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline.

Fen Xiong, Kaiyan Gong, Hangying Xu, Yingxin Tu, Jiahui Lu, Yiyang Zhou, Wenting He, Wenqing Li, Chen Li, Liangcai Zhao, Hongchang Gao, Hong Zheng.

   INTRODUCTION: Type 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear.
OBJECTIVES: The purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics.
METHODS: We developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice.
RESULTS: The results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus.
CONCLUSION: Our results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus.

Keywords:  Brain; Cognition; Diabetes; Lipidomics; Metabolomics; Neuroinflammation

DOI:  https://doi.org/10.1016/j.jare.2022.02.011
J Neurochem. 2022 Dec 29.

Apolipoprotein E4 inhibits γ-secretase activity via binding to the γ-secretase complex.

Yang Sun, Sadequl Islam, Yuan Gao, Tomohisa Nakamura, Kun Zou, Makoto Michikawa.

The mechanisms of amyloid accumulation in familial Alzheimer's disease (FAD) and sporadic AD (SAD) are controversial. In FAD, mutations in presenilin (PSEN) impair γ-secretase activity and lead to abnormal amyloid β-protein (Aβ) production, thereby increasing the Aβ42/40 ratio. SAD is postulated to be caused by decreased Aβ clearance of apolipoprotein E4 (APOE4), the strongest risk factor for SAD. However, whether intracellular APOE4 affects Aβ production is unclear. Using APOE3 and APOE4 knock-in (KI) mouse brain and primary cultured fibroblasts from these mice, in this study, we demonstrated that APOE3 and APOE4 bind to the γ-secretase complex and isoform-dependently regulate its activity and Aβ production. We found that Aβ40 levels and γ-secretase activity were higher in APOE knockout mouse brain than wild-type mouse brain. APOE4-KI fibroblasts had significant lower Aβ levels and γ-secretase activity but higher Aβ42/40 ratio compared with APOE3-KI cells, indicating that APOE4-KI reduces Aβ production by inhibiting γ-secretase activity. Interestingly, the levels of γ-secretase complex bound to APOE4 are higher than those bound to APOE3, and the levels of γ-secretase complex in the brain and fibroblasts of APOE4-KI mice were higher than those of APOE3-KI mice. Taken together, our findings demonstrate that intracellular APOE4 inhibits Aβ production, more preferentially inhibits Aβ40 production, and thereby induces an increase in the Aβ42/40 ratio via binding to the γ-secretase complex. These results suggest a novel mechanism in which intracellular APOE4 contributes to the pathogenesis of SAD by inhibiting γ-secretase activity.

DOI: https://doi.org/10.1111/jnc.15750
Cell. 2022 Dec 21. pii: S0092-8674(22)01523-9. [Epub ahead of print]

Molecular and spatial signatures of mouse brain aging at single-cell resolution.

William E Allen, Timothy R Blosser, Zuri A Sullivan, Catherine Dulac, Xiaowei Zhuang.

  The diversity and complex organization of cells in the brain have hindered systematic characterization of age-related changes in its cellular and molecular architecture, limiting our ability to understand the mechanisms underlying its functional decline during aging. Here, we generated a high-resolution cell atlas of brain aging within the frontal cortex and striatum using spatially resolved single-cell transcriptomics and quantified changes in gene expression and spatial organization of major cell types in these regions over the mouse lifespan. We observed substantially more pronounced changes in cell state, gene expression, and spatial organization of non-neuronal cells over neurons. Our data revealed molecular and spatial signatures of glial and immune cell activation during aging, particularly enriched in the subcortical white matter, and identified both similarities and notable differences in cell-activation patterns induced by aging and systemic inflammatory challenge. These results provide critical insights into age-related decline and inflammation in the brain.

Keywords:  LPS; MERFISH; astrocyte; brain aging; inflammation; microglia; oligodendrocyte; single-cell RNA sequencing; single-cell transcriptomics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.cell.2022.12.010
Glia. 2022 Dec 30.

Early microglial response, myelin deterioration and lethality in mice deficient for very long chain ceramide synthesis in oligodendrocytes.

Jonathan D Teo, Oana C Marian, Alanna G Spiteri, Madeline Nicholson, Huitong Song, Jasmine X Y Khor, Holly P McEwen, Anjie Ge, Monokesh K Sen, Laura Piccio, Jessica L Fletcher, Nicholas J C King, Simon S Murray, Jens C Brüning, Anthony S Don.

  The sphingolipids galactosylceramide (GalCer), sulfatide (ST) and sphingomyelin (SM) are essential for myelin stability and function. GalCer and ST are synthesized mostly from C22-C24 ceramides, generated by Ceramide Synthase 2 (CerS2). To clarify the requirement for C22-C24 sphingolipid synthesis in myelin biosynthesis and stability, we generated mice lacking CerS2 specifically in myelinating cells (CerS2ΔO/ΔO ). At 6 weeks of age, normal-appearing myelin had formed in CerS2ΔO/ΔO mice, however there was a reduction in myelin thickness and the percentage of myelinated axons. Pronounced loss of C22-C24 sphingolipids in myelin of CerS2ΔO/ΔO mice was compensated by greatly increased levels of C18 sphingolipids. A distinct microglial population expressing high levels of activation and phagocytic markers such as CD64, CD11c, MHC class II, and CD68 was apparent at 6 weeks of age in CerS2ΔO/ΔO mice, and had increased by 10 weeks. Increased staining for denatured myelin basic protein was also apparent in 6-week-old CerS2ΔO/ΔO mice. By 16 weeks, CerS2ΔO/ΔO mice showed pronounced myelin atrophy, motor deficits, and axon beading, a hallmark of axon stress. 90% of CerS2ΔO/ΔO mice died between 16 and 26 weeks of age. This study highlights the importance of sphingolipid acyl chain length for the structural integrity of myelin, demonstrating how a modest reduction in lipid chain length causes exposure of a denatured myelin protein epitope and expansion of phagocytic microglia, followed by axon pathology, myelin degeneration, and motor deficits. Understanding the molecular trigger for microglial activation should aid the development of therapeutics for demyelinating and neurodegenerative diseases.

Keywords:  CERS2; ceramide; demyelination; lipid; microglia; myelin; sphingolipid

DOI:  https://doi.org/10.1002/glia.24329
Life Sci. 2022 Dec 22. pii: S0024-3205(22)01016-5. [Epub ahead of print]314 121316

High fat diet exacerbates long-term metabolic, neuropathological, and behavioral derangements in an experimental mouse model of traumatic brain injury.

Stanley Ibeh, Nour-Mounira Z Bakkar, Fatima Ahmad, Judith Nwaiwu, Chloe Barsa, Sarine Mekhjian, Mohammad Amine Reslan, Ali H Eid, Hayat Harati, Sanaa Nabha, Yehia Mechref, Ahmed F El-Yazbi, Firas Kobeissy.

   AIMS: Traumatic brain injury (TBI) constitutes a serious public health concern. Although TBI targets the brain, it can exert several systemic effects which can worsen the complications observed in TBI subjects. Currently, there is no FDA-approved therapy available for its treatment. Thus, there has been an increasing need to understand other factors that could modulate TBI outcomes. Among the factors involved are diet and lifestyle. High-fat diets (HFD), rich in saturated fat, have been associated with adverse effects on brain health.
MAIN METHODS: To study this phenomenon, an experimental mouse model of open head injury, induced by the controlled cortical impact was used along with high-fat feeding to evaluate the impact of HFD on brain injury outcomes. Mice were fed HFD for a period of two months where several neurological, behavioral, and molecular outcomes were assessed to investigate the impact on chronic consequences of the injury 30 days post-TBI.
KEY FINDINGS: Two months of HFD feeding, together with TBI, led to a notable metabolic, neurological, and behavioral impairment. HFD was associated with increased blood glucose and fat-to-lean ratio. Spatial learning and memory, as well as motor coordination, were all significantly impaired. Notably, HFD aggravated neuroinflammation, oxidative stress, and neurodegeneration. Also, cell proliferation post-TBI was repressed by HFD, which was accompanied by an increased lesion volume.
SIGNIFICANCE: Our research indicated that chronic HFD feeding can worsen functional outcomes, predispose to neurodegeneration, and decrease brain recovery post-TBI. This sheds light on the clinical impact of HFD on TBI pathophysiology and rehabilitation as well.

Keywords:  High-fat diet; Metabolic syndrome; Neurodegeneration; Neuroinflammation; Oxidative stress; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.lfs.2022.121316
Proc Natl Acad Sci U S A. 2023 Jan 03. 120(1): e2209990120

Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.

Luo-Qi Zhou, Ming-Hao Dong, Zi-Wei Hu, Yue Tang, Yun-Hui Chu, Man Chen, Sheng Yang, Zhi Chen, Long-Jun Wu, Wei Wang, Chuan Qin, Dai-Shi Tian.

  Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Keywords:  autophagic–lysosomal pathway; conjugated linoleic acid; demyelination; lipid metabolism; microglia

DOI:  https://doi.org/10.1073/pnas.2209990120
Angew Chem Int Ed Engl. 2022 Dec 27.

Tandem Mass Spectrometry Imaging Enables High Definition for Mapping Lipids in Tissues.

Xiangyu Guo, Wenbo Cao, Xiaomin Fan, Zhiying Guo, Donghui Zhang, Haoyue Zhang, Xiaoxiao Ma, Jiahong Dong, Yunfang Wang, Wenpeng Zhang, Zheng Ouyang.

  Mass spectrometry imaging (MSI) of lipids in biological tissues is useful for correlating molecular distribution with pathological results, which could provide useful information for both biological research and disease diagnosis. It is well understood that the lipidome could not be clearly deciphered without tandem mass spectrometry analysis, but this is challenging to achieve in MSI due to the limitation in sample amount at each image spot. Here we develop a multiplexed MS2 imaging (MS2I) method that can provide MS2 images for 10 lipid species or more for each sampling spot, providing spatial structural lipidomic information. Coupling with on-tissue photochemical derivatization, imaging of 20 phospholipid C=C location isomers is also realized, showing enhanced molecular images with high definition in structure for mouse brain and human liver cancer tissue sections. Spatially mapped t-distributed stochastic neighbor embedding has also been adopted to visualize the tumor margin with enhancement by structural lipidomic information.

Keywords:  Lipidomics; MS/MS imaging; lipid biomarker; lipid isomer; mass spectrometry imaging

DOI:  https://doi.org/10.1002/anie.202214804