bims-medebr 2022-07-10 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–07–10
ten papers selected by
Regina F. Fernández, Johns Hopkins University

DHA Ameliorates Cognitive Ability, Reduces Amyloid Deposition, and Nerve Fiber Production in Alzheimer's Disease.
Effects of Dietary n-3 LCPUFA Supplementation on the Hippocampus of Aging Female Mice: Impact on Memory, Lipid Raft-Associated Glutamatergic Receptors and Neuroinflammation.
DHCR24 Knockdown Induces Tau Hyperphosphorylation at Thr181, Ser199, Ser262, and Ser396 Sites via Activation of the Lipid Raft-Dependent Ras/MEK/ERK Signaling Pathway in C8D1A Astrocytes.
Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses.
An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD).
Metabolic Mechanisms Connecting Alzheimer's and Parkinson's Diseases: Potential Avenues for Novel Therapeutic Approaches.
Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders.
Arachidonic Acid Cascade and Eicosanoid Production Are Elevated While LTC4 Synthase Modulates the Lipidomics Profile in the Brain of the HIVgp120-Transgenic Mouse Model of NeuroHIV.
Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors.
A Short-Term Sucrose Diet Impacts Cell Proliferation of Neural Precursors in the Adult Hypothalamus.

Front Nutr. 2022 ;9 852433

DHA Ameliorates Cognitive Ability, Reduces Amyloid Deposition, and Nerve Fiber Production in Alzheimer's Disease.

Min Xiao, Wei Xiang, Yashu Chen, Nan Peng, Xiubo Du, Shuhuan Lu, Yao Zuo, Boling Li, Yonggang Hu, Xiangyu Li.

   Background: The etiology of Alzheimer's disease (AD) is very complex. Docosahexaenoic acid (DHA) is important in cognitive ability and nervous system development. A limited number of studies have evaluated the efficacy of DHA in the treatment of AD.
Introduction: We detected neurofibrillary tangles (NFT) in the hippocampus and cortex of transgenic mice brain through silver glycine staining. We determined the activity of neurons by staining Nissl bodies, used liquid NMR to detect metabolites in the brain, and functional magnetic resonance imaging results to observe the connection signal value between brain regions.
Materials and Methods: We fed 3-month-old APP/PS1 double transgenic mice with DHA mixed feeds for 4 months to assess the effects of DHA on cognitive ability in AD mice through the Morris water maze and open field tests. To evaluate its effects with AD pathology, continuous feeding was done until the mice reached 9 months of age.
Results: Compared to AD mice, escape latency significantly decreased on the fifth day while swimming speed, target quadrant stay time, and the crossing number of platforms increased by varying degrees after DHA treatment. Brain tissue section staining revealed that DHA significantly reduced Aβ and nerve fibers in the brain of AD mice.
Conclusion: DHA significantly reduced the deposition of Aβ in the brain and inhibited the production of nerve fibers, thereby increasing cognitive abilities in AD mice. In addition, DHA suppressed blood lipid levels, and restored uric acid and urea levels, implying that DHA is a potential therapeutic option for early AD.

Keywords:  Alzheimer’s disease; Aβ; NFT; PUFAs; docosahexaenoic acid; liquid NMR; neurodegenerative disease; omega-3

DOI:  https://doi.org/10.3389/fnut.2022.852433
Int J Mol Sci. 2022 Jul 04. pii: 7430. [Epub ahead of print]23(13):

Effects of Dietary n-3 LCPUFA Supplementation on the Hippocampus of Aging Female Mice: Impact on Memory, Lipid Raft-Associated Glutamatergic Receptors and Neuroinflammation.

Lucas Taoro-González, Daniel Pereda, Catalina Valdés-Baizabal, Miriam González-Gómez, José A Pérez, Fátima Mesa-Herrera, Ana Canerina-Amaro, Herminia Pérez-González, Covadonga Rodríguez, Mario Díaz, Raquel Marin.

  Long-chain polyunsaturated fatty acids (LCPUFA), essential molecules whose precursors must be dietary supplied, are highly represented in the brain contributing to numerous neuronal processes. Recent findings have demonstrated that LCPUFA are represented in lipid raft microstructures, where they favor molecular interactions of signaling complexes underlying neuronal functionality. During aging, the brain lipid composition changes affecting the lipid rafts' integrity and protein signaling, which may induce memory detriment. We investigated the effect of a n-3 LCPUFA-enriched diet on the cognitive function of 6- and 15-months-old female mice. Likewise, we explored the impact of dietary n-3 LCPUFAs on hippocampal lipid rafts, and their potential correlation with aging-induced neuroinflammation. Our results demonstrate that n-3 LCPUFA supplementation improves spatial and recognition memory and restores the expression of glutamate and estrogen receptors in the hippocampal lipid rafts of aged mice to similar profiles than young ones. Additionally, the n-3 LCPUFA-enriched diet stabilized the lipid composition of the old mice's hippocampal lipid rafts to the levels of young ones and reduced the aged-induced neuroinflammatory markers. Hence, we propose that n-3 LCPUFA supplementation leads to beneficial cognitive performance by "rejuvenating" the lipid raft microenvironment that stabilizes the integrity and interactions of memory protein players embedded in these microdomains.

Keywords:  aging; diet; hippocampus; lipid rafts; long-chain polyunsaturated fatty acids supplementation; memory; neuroinflammation

DOI:  https://doi.org/10.3390/ijms23137430
Mol Neurobiol. 2022 Jul 08.

DHCR24 Knockdown Induces Tau Hyperphosphorylation at Thr181, Ser199, Ser262, and Ser396 Sites via Activation of the Lipid Raft-Dependent Ras/MEK/ERK Signaling Pathway in C8D1A Astrocytes.

Meiting Mai, Xiaorou Guo, Yue Huang, Wenbin Zhang, Yixuan Xu, Ying Zhang, Xiaojing Bai, Junfeng Wu, Hengbing Zu.

  The synthetase 3β-hydroxysterol-Δ24 reductase (DHCR24) is a key regulator involved in cholesterol synthesis and homeostasis. A growing body of evidence indicates that DHCR24 is downregulated in the brain of various models of Alzheimer's disease (AD), such as astrocytes isolated from AD mice. For the past decades, astrocytic tau pathology has been found in AD patients, while the origin of phosphorylated tau in astrocytes remains unknown. A previous study suggests that downregulation of DHCR24 is associated with neuronal tau hyperphosphorylation. Herein, the present study is to explore whether DHCR24 deficiency can also affect tau phosphorylation in astrocytes. Here, we showed that DHCR24 knockdown could induce tau hyperphosphorylation at Thr181, Ser199, Thr231, Ser262, and Ser396 sites in C8D1A astrocytes. Meanwhile, we found that DHCR24-silencing cells had reduced the level of free cholesterol in the plasma membrane and intracellular organelles, as well as cholesterol esters. Furthermore, reduced cellular cholesterol level caused a decreased level of the caveolae-associated protein, cavin1, which disrupted lipid rafts/caveolae and activated rafts/caveolae-dependent Ras/MEK/ERK signaling pathway. In contrast, overexpression of DHCR24 prevented the overactivation of Ras/MEK/ERK signaling by increasing cellular cholesterol content, therefore decreasing tau hyperphosphorylation in C8D1A astrocytes. Herein, we firstly found that DHCR24 knockdown can lead to tau hyperphosphorylation in the astrocyte itself by activating lipid raft-dependent Ras/MEK/ERK signaling, which might contribute to the pathogenesis of AD and other degenerative tauopathies.

Keywords:  Alzheimer’s disease; Astrocyte; Cholesterol; DHCR24; Tau hyperphosphorylation

DOI:  https://doi.org/10.1007/s12035-022-02945-w
Front Chem. 2022 ;10 892284

Administration of Phosphonate Inhibitors of Dehydrogenases of 2-Oxoglutarate and 2-Oxoadipate to Rats Elicits Target-Specific Metabolic and Physiological Responses.

Victoria I Bunik, Artem V Artiukhov, Alexey V Kazantsev, Vasily A Aleshin, Alexandra I Boyko, Alexander L Ksenofontov, Nikolay V Lukashev, Anastasia V Graf.

  In vitro and in cell cultures, succinyl phosphonate (SP) and adipoyl phosphonate (AP) selectively target dehydrogenases of 2-oxoglutarate (OGDH, encoded by OGDH/OGDHL) and 2-oxoadipate (OADH, encoded by DHTKD1), respectively. To assess the selectivity in animals, the effects of SP, AP, and their membrane-penetrating triethyl esters (TESP and TEAP) on the rat brain metabolism and animal physiology are compared. Opposite effects of the OGDH and OADH inhibitors on activities of OGDH, malate dehydrogenase, glutamine synthetase, and levels of glutamate, lysine, citrulline, and carnosine are shown to result in distinct physiological responses. ECG is changed by AP/TEAP, whereas anxiety is increased by SP/TESP. The potential role of the ester moiety in the uncharged precursors of the 2-oxo acid dehydrogenase inhibitors is estimated. TMAP is shown to be less efficient than TEAP, in agreement with lower lipophilicity of TMAP vs. TEAP. Non-monotonous metabolic and physiological impacts of increasing OADH inhibition are revealed. Compared to the non-treated animals, strong inhibition of OADH decreases levels of tryptophan and beta-aminoisobutyrate and activities of malate dehydrogenase and pyruvate dehydrogenase, increasing the R-R interval of ECG. Thus, both metabolic and physiological actions of the OADH-directed inhibitors AP/TEAP are different from those of the OGDH-directed inhibitors SP/TESP, with the ethyl ester being more efficient than methyl ester.

Keywords:  2-oxoadipate dehydrogenase; 2-oxoglutarate dehydrogenase; DHTKD1; phosphonate analog of 2-oxo acid; regulation of brain metabolism

DOI:  https://doi.org/10.3389/fchem.2022.892284
Int J Mol Sci. 2022 Jun 27. pii: 7144. [Epub ahead of print]23(13):

An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD).

Sara Tucci.

  Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADD/MTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective β-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADD/MTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADD/MTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype.

Keywords:  LCHADD; lipidomics; long-chain fatty acid oxidation disorders; neurodegeneration; sphyngomyelines and ceramides

DOI:  https://doi.org/10.3390/ijms23137144
Front Mol Biosci. 2022 ;9 929328

Metabolic Mechanisms Connecting Alzheimer's and Parkinson's Diseases: Potential Avenues for Novel Therapeutic Approaches.

Jerry R Colca, Brian N Finck.

  Alzheimer's (AD) and Parkinson's Diseases (PD) are common neurodegenerative disorders growing in incidence and prevalence and for which there are no disease-modifying treatments. While there are considerable complexities in the presentations of these diseases, the histological pictures of these pathologies, as well as several rare genetic predispositions for each, point to the involvement of maladaptive protein processing and inflammation. Importantly, the common presentations of AD and PD are connected to aging and to dysmetabolism, including common co-diagnosis of metabolic syndrome or diabetes. Examination of anti-diabetic therapies in preclinical models and in some observational clinical studies have suggested effectiveness of the first generation insulin sensitizer pioglitazone in both AD and PD. Recently, the mitochondrial pyruvate carrier (MPC) was shown to be a previously unrecognized target of pioglitazone. New insulin sensitizers are in development that can be dosed to full engagement of this previously unappreciated mitochondrial target. Here we review molecular mechanisms that connect modification of pyruvate metabolism with known liabilities of AD and PD. The mechanisms involve modification of autophagy, inflammation, and cell differentiation in various cell types including neurons, glia, macrophages, and endothelium. These observations have implications for the understanding of the general pathology of neurodegeneration and suggest general therapeutic approaches to disease modification.

Keywords:  Alzhaimer’s disease (AD); Parkinsion’s disease; autophagy; inflammation; mitochondria

DOI:  https://doi.org/10.3389/fmolb.2022.929328
Int J Mol Sci. 2022 Jun 30. pii: 7263. [Epub ahead of print]23(13):

Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders.

Jannik Prasuhn, Liesa Kunert, Norbert Brüggemann.

  Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs. This narrative review highlights various neuroimaging methods to probe mitochondrial dysfunction. We provide a general overview of the current biological understanding of mitochondrial dysfunction in degenerative brain disorders and how distinct neuroimaging methods can be employed to map disease-related changes. The reviewed methodological spectrum includes positron emission tomography, magnetic resonance, magnetic resonance spectroscopy, and near-infrared spectroscopy imaging, and how these methods can be applied to study alterations in oxidative phosphorylation and oxidative stress. We highlight the advantages and shortcomings of the different neuroimaging methods and discuss the necessary steps to use these for future research. This review stresses the importance of neuroimaging methods to gain deepened insights into mitochondrial dysfunction in vivo, its role as a critical disease mechanism in neurodegenerative diseases, the applicability for patient stratification in interventional trials, and the quantification of individual treatment responses. The in vivo assessment of mitochondrial dysfunction is a crucial prerequisite for providing individualized treatments for neurodegenerative disorders.

Keywords:  Parkinson’s disease (PD); mitochondria; mitochondrial dysfunction; neurodegeneration; neuroimaging

DOI:  https://doi.org/10.3390/ijms23137263
Cells. 2022 Jul 05. pii: 2123. [Epub ahead of print]11(13):

Arachidonic Acid Cascade and Eicosanoid Production Are Elevated While LTC4 Synthase Modulates the Lipidomics Profile in the Brain of the HIVgp120-Transgenic Mouse Model of NeuroHIV.

Nina Y Yuan, Ricky Maung, Ziying Xu, Xianlin Han, Marcus Kaul.

   BACKGROUND: Combination antiretroviral therapy (cART) has transformed HIV infection from a terminal disease to a manageable chronic health condition, extending patients' life expectancy to that of the general population. However, the incidence of HIV-associated neurocognitive disorders (HANDs) has persisted despite virological suppression. Patients with HIV display persistent signs of immune activation and inflammation despite cART. The arachidonic acid (AA) cascade is an important immune response system responsible for both pro- and anti-inflammatory processes.
METHODS: Lipidomics, mRNA and Western blotting analysis provide valuable insights into the molecular mechanisms surrounding arachidonic acid metabolism and the resulting inflammation caused by perturbations thereof.
RESULTS: Here, we report the presence of inflammatory eicosanoids in the brains of a transgenic mouse model of NeuroHIV that expresses soluble HIV-1 envelope glycoprotein in glial cells (HIVgp120tg mice). Additionally, we report that the effect of LTC4S knockout in HIVgp120tg mice resulted in the sexually dimorphic transcription of COX- and 5-LOX-related genes. Furthermore, the absence of LTC4S suppressed ERK1/2 and p38 MAPK signaling activity in female mice only. The mass spectrometry-based lipidomic profiling of these mice reveals beneficial alterations to lipids in the brain.
CONCLUSION: Targeting the AA cascade may hold potential in the treatment of neuroinflammation observed in NeuroHIV and HANDs.

Keywords:  HANDs; HIV; LTC4S; arachidonic acid; cell signaling; eicosanoids; lipidomics; mRNA; neuroinflammation; sexual dimorphism

DOI:  https://doi.org/10.3390/cells11132123
Neural Regen Res. 2023 Jan;18(1): 5-17

Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors.

Najam A Sharif.

  Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and thromboxane-A2 interact with five major receptors (and their sub-types) to elicit specific downstream cellular and tissue actions. In general, prostaglandins have been associated with pain, inflammation, and edema when they are present at high local concentrations and involved on a chronic basis. However, in acute settings, certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation, providing cellular protection, regulating sleep, and enhancing blood flow, to lowering intraocular pressure to prevent the development of glaucoma, a blinding disease. Several classes of prostaglandins are implicated (or are considered beneficial) in certain central nervous system dysfunctions (e.g., Alzheimer's, Parkinson's, and Huntington's diseases; amyotrophic lateral sclerosis and multiple sclerosis; stroke, traumatic brain injuries and pain) and in ocular disorders (e.g., ocular hypertension and glaucoma; allergy and inflammation; edematous retinal disorders). This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease, and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists, polyunsaturated fatty acids, and cyclooxygenase inhibitors.

Keywords:  AL-8810; axon; brain; central nervous system; cyclooxygenase inhibitors; neuron; neuroprotection; ocular; polyunsaturated fatty acids; prostaglandins

DOI:  https://doi.org/10.4103/1673-5374.343887
Nutrients. 2022 Jun 21. pii: 2564. [Epub ahead of print]14(13):

A Short-Term Sucrose Diet Impacts Cell Proliferation of Neural Precursors in the Adult Hypothalamus.

Antonia Recabal, Sergio López, Magdiel Salgado, Alejandra Palma, Ana M Obregón, Roberto Elizondo-Vega, Juan C Sáez, María Á García-Robles.

  Radial glia-like cells in the hypothalamus and dorsal vagal complex are neural precursors (NPs) located near subventricular organs: median eminence and area postrema, respectively. Their strategic position can detect blood-borne nutrients, hormones, and mitogenic signals. Hypothalamic NPs increase their proliferation with a mechanism that involves hemichannel (HC) activity. NPs can originate new neurons in response to a short-term high-fat diet as a compensatory mechanism. The effects of high carbohydrate Western diets on adult neurogenesis are unknown. Although sugars are usually consumed as sucrose, more free fructose is now incorporated into food items. Here, we studied the proliferation of both types of NPs in Sprague Dawley rats exposed to a short-term high sucrose diet (HSD) and a control diet. In tanycyte cultures, we evaluated the effects of glucose and fructose and a mix of both hexoses on HC activity. In rats fed an HSD, we observed an increase in the proliferative state of both precursors. Glucose, either in the presence or absence of fructose, but not fructose alone, induced in vitro HC activity. These results should broaden the understanding of the nutrient monitoring capacity of NPs in reacting to changes in feeding behavior, specifically to high sugar western diets.

Keywords:  feeding behavior; fructose; neuronal precursor cell; proliferation; sucrose; tanycyte

DOI:  https://doi.org/10.3390/nu14132564