bims-brabim 2022-01-09 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2022–01–09
thirty papers selected by
João Victor Cabral-Costa, University of São Paulo

Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?
Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway.
Glucose sparing by glycogenolysis (GSG) determines the relationship between brain metabolism and neurotransmission.
Microglial metabolic flexibility: emerging roles for lactate.
MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes.
Transcranial photobiomodulation therapy ameliorates perioperative neurocognitive disorder through modulation of mitochondrial function in aged mice.
The Effect of Sleep Deprivation and Subsequent Recovery Period on the Synaptic Proteome of Rat Cerebral Cortex.
Multidimensional dynamics of the proteome in the neurodegenerative and aging mammalian brain.
Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via the ABCA1 transmembrane transport system in APP/PS1 double transgenic mice.
Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol.
HDAC6 inhibition reverses long-term doxorubicin-induced cognitive dysfunction by restoring microglia homeostasis and synaptic integrity.
Hepcidin Promoted Ferroptosis through Iron Metabolism which Is Associated with DMT1 Signaling Activation in Early Brain Injury following Subarachnoid Hemorrhage.
16pdel lipid changes in iPSC-derived neurons and function of FAM57B in lipid metabolism and synaptogenesis.
Astrocytic glycogen mobilization participates in salvianolic acid B-mediated neuroprotection against reperfusion injury after ischemic stroke.
Centella asiatica Alleviates AlCl3-induced Cognitive Impairment, Oxidative Stress, and Neurodegeneration by Modulating Cholinergic Activity and Oxidative Burden in Rat Brain.
The protective effect of Metformin/Donepezil in diabetic mice brain: evidence from bioinformatics analysis and experiments.
Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function.
Downregulation of Bdnf Expression in Adult Mice Causes Body Weight Gain.
Lipid Metabolism and Alzheimer's Disease: Clinical Evidence, Mechanistic Link and Therapeutic Promise.
Ellagic acid prevents streptozotocin-induced hippocampal damage and memory loss in rats by stimulating Nrf2 and nuclear factor-κB, and activating insulin receptor substrate/PI3K/Akt axis.
Puerarin alleviates cadmium-induced mitochondrial mass decrease by inhibiting PINK1-Parkin and Nix-mediated mitophagy in rat cortical neurons.
Activation of α7 Nicotinic Acetylcholine Receptor by its Selective Agonist Improved Learning and Memory of Amyloid Precursor Protein/Presenilin 1 (APP/PS1) Mice via the Nrf2/HO-1 Pathway.
Isoform-dependent lysosomal degradation and internalization of Apolipoprotein E requires autophagy proteins.
Neuronal regulation of glucagon secretion and gluconeogenesis.
mtIF3 is locally translated in axons and regulates mitochondrial translation for axonal growth.
Neuroinflammation and Behavioral Deficit in Rotenone-Induced Neurotoxicity in Rats and the Possible Effects of Butanolic Extract of Centaurea Africana.
Manipulations of Glutathione Metabolism Modulate IP3-Mediated Store-Operated Ca2+ Entry on Astroglioma Cell Line.
Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development.
The hypothalamic paraventricular nucleus as a central hub for the estrogenic modulation of neuroendocrine function and behavior.
Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

Front Mol Neurosci. 2021 ;14 788695

Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

Raja Elizabeth Estes, Bernice Lin, Arnav Khera, Marie Ynez Davis.

  Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.

Keywords:  Alzheimer’s disease; Parkinson’s disease; ceramide; extracellular vesicle; glia; glucocerebrosidase (GBA); lipid metabolism; protein aggregation and propagation

DOI:  https://doi.org/10.3389/fnmol.2021.788695
Chin J Physiol. 2021 Nov-Dec;64(6):64(6): 266-273

Nicotinamide adenine dinucleotide promotes synaptic plasticity gene expression through regulation N-methyl-D-aspartate receptor/Ca2+/Erk1/2 pathway.

Xiao-Yu Liu, Rui-Heng Song, Tao Li, Xu Tan, Xiang-Hong Zhang, Kun-Kun Pang, Jian-Yu Shen, Qing-Wei Yue, Jin-Hao Sun.

  Nicotinamide adenine dinucleotide (NADH) has been reported to regulate synaptic plasticity recently, while its role in this process remains unclear. To explore the contribution and the underlying mechanisms of NADH regulating synaptic plasticity, here, we examined NADH's effect on immediate-early response genes (IEGs) expressions, including C-Fos and Arc in primary cultured cortical neurons and the frontal cortex of mouse brain. Our results showed that NADH promoted IEGs expression and that the C-Fos and Arc levels are increased in primary cultured cortical neurons, which is almost completely blocked by N-methyl-D-aspartate receptor (NMDAR) inhibitor, MK-801. Moreover, NADH significantly increased intracellular Ca2+ levels and the phosphorylation of Erk1/2, a downstream molecule of the NMDAR. Furthermore, NADH also significantly increased IEGs expression in vivo, accompanied by the changes of Ca2+ in neurons and activation of excitatory neurons in the mouse frontal cortex. In conclusion, this study indicates that NADH can promote the expression of synaptic plasticity-related IEGs through the NMDAR/Ca2+/Erk1/2 pathway, which provides a new way to understand the regulatory role of NADH in synaptic plasticity.

Keywords:  Immediate early gene; neuron; nicotinamide adenine dinucleotide; synaptic plasticity

DOI:  https://doi.org/10.4103/cjp.cjp_42_21
J Cereb Blood Flow Metab. 2022 Jan 07. 271678X211064399

Glucose sparing by glycogenolysis (GSG) determines the relationship between brain metabolism and neurotransmission.

Douglas L Rothman, Gerald A Dienel, Kevin L Behar, Fahmeed Hyder, Mauro DiNuzzo, Federico Giove, Silvia Mangia.

  Over the last two decades, it has been established that glucose metabolic fluxes in neurons and astrocytes are proportional to the rates of the glutamate/GABA-glutamine neurotransmitter cycles in close to 1:1 stoichiometries across a wide range of functional energy demands. However, there is presently no mechanistic explanation for these relationships. We present here a theoretical meta-analysis that tests whether the brain's unique compartmentation of glycogen metabolism in the astrocyte and the requirement for neuronal glucose homeostasis lead to the observed stoichiometries. We found that blood-brain barrier glucose transport can be limiting during activation and that the energy demand could only be met if glycogenolysis supports neuronal glucose metabolism by replacing the glucose consumed by astrocytes, a mechanism we call Glucose Sparing by Glycogenolysis (GSG). The predictions of the GSG model are in excellent agreement with a wide range of experimental results from rats, mice, tree shrews, and humans, which were previously unexplained. Glycogenolysis and glucose sparing dictate the energy available to support neuronal activity, thus playing a fundamental role in brain function in health and disease.

Keywords:  Astrocytes; energy metabolism; glucose; glycogen; lactate; neurochemistry

DOI:  https://doi.org/10.1177/0271678X211064399
Trends Endocrinol Metab. 2022 Jan 04. pii: S1043-2760(21)00284-8. [Epub ahead of print]

Microglial metabolic flexibility: emerging roles for lactate.

Katia Monsorno, An Buckinx, Rosa C Paolicelli.

  Microglia, the resident macrophages of the central nervous system (CNS), play important functions in the healthy and diseased brain. In the emerging field of immunometabolism, progress has been made in understanding how cellular metabolism can orchestrate the key responses of tissue macrophages, such as phagocytosis and inflammation. However, very little is known about the metabolic control of microglia. Lactate, now recognized as a crucial metabolite and a central substrate in metabolic flexibility, is emerging not only as a novel bioenergetic fuel for microglial metabolism but also as a potential modulator of cellular function. Parallels with macrophages will help in understanding how microglial lactate metabolism is implicated in brain physiology and pathology, and how it could be targeted for therapeutic purposes.

Keywords:  CNS disease; lactate; metabolism; microglia; synaptic function

DOI:  https://doi.org/10.1016/j.tem.2021.12.001
J Neuroinflammation. 2022 Jan 06. 19(1): 10

MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes.

Nicholas W Kieran, Rahul Suresh, Marie-France Dorion, Adam MacDonald, Manon Blain, Dingke Wen, Shih-Chieh Fuh, Fari Ryan, Roberto J Diaz, Jo Anne Stratton, Samuel K Ludwin, Joshua A Sonnen, Jack Antel, Luke M Healy.

   BACKGROUND: Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest.
METHODS: Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse.
RESULTS: Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses. A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b (Sema5b).
CONCLUSIONS: We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.

Keywords:  Astrocyte; Hypoxia; Inflammation; Ischemia; MicroRNA-210; Multiple sclerosis; Stroke

DOI:  https://doi.org/10.1186/s12974-021-02373-y
Neuroscience. 2021 Dec 31. pii: S0306-4522(21)00664-3. [Epub ahead of print]

Transcranial photobiomodulation therapy ameliorates perioperative neurocognitive disorder through modulation of mitochondrial function in aged mice.

Xiaojun Zhang, Wensi Wu, Yuelian Luo, Zhi Wang.

  Perioperative neurocognitive disorder (PND) is a serious nervous system complication characterized by progressive cognitive impairment, especially in geriatric population. However, the neuropathogenesis of PND is complex, and there are no approved disease-modifying therapeutic options. Mitochondrial dysfunction has been demonstrated to contribute to the occurrence and development of PND. Transcranial near-infrared (tNIR) light treatment helps to improve mitochondrial dysfunction and enhance cognition, but its effect on PND remains unclear. Here, we evaluated the effect of tNIR light treatment on PND caused by anesthesia and surgery in aged mice. We built the PND models with 18-month C57BL/6 male mice by exploratory laparotomy under isoflurane inhalation anesthesia, and treated by tNIR light with wavelength 810 nm for 2 weeks. The short-term and long-term changes in cognitive function were analyzed by behavioral tests. We further explored the effects of tNIR light on mitochondria, synapses, neurons, and signaling pathways through different experimental methods. The results demonstrated that the cognitive impairment and mitochondrial dysfunction in PND mice were ameliorated after tNIR light treatment. Further experiments demonstrated that photobiomodulation therapy (PBMT) increased synapse-related protein expression, neuronal survival, and protected synapse from depletion. Moreover, downregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) were increased after tNIR light treatment. Our results suggested that tNIR light was an effective treatment of PND through PBMT effect, accompanied by synaptic and neuronal improvement. The improvement of mitochondrial dysfunction mediated by SIRT1/PGC-1α signaling pathway might participate in this process. Those findings might provide a novel and noninvasive therapeutic target for PND.

Keywords:  SIRT1/PGC-1α pathway; mitochondrial dysfunction; perioperative neurocognitive disorder; photobiomodulation therapy; synapse; transcranial near-infrared light

DOI:  https://doi.org/10.1016/j.neuroscience.2021.12.033
Mol Neurobiol. 2022 Jan 05.

The Effect of Sleep Deprivation and Subsequent Recovery Period on the Synaptic Proteome of Rat Cerebral Cortex.

Péter Gulyássy, Katalin Todorov-Völgyi, Vilmos Tóth, Balázs A Györffy, Gina Puska, Attila Simor, Gábor Juhász, László Drahos, Katalin Adrienna Kékesi.

  Sleep deprivation (SD) is commonplace in the modern way of life and has a substantial social, medical, and human cost. Sleep deprivation induces cognitive impairment such as loss of executive attention, working memory decline, poor emotion regulation, increased reaction times, and higher cognitive functions are particularly vulnerable to sleep loss. Furthermore, SD is associated with obesity, diabetes, cardiovascular diseases, cancer, and a vast majority of psychiatric and neurodegenerative disorders are accompanied by sleep disturbances. Despite the widespread scientific interest in the effect of sleep loss on synaptic function, there is a lack of investigation focusing on synaptic transmission on the proteome level. In the present study, we report the effects of SD and recovery period (RP) on the cortical synaptic proteome in rats. Synaptosomes were isolated after 8 h of SD performed by gentle handling and after 16 h of RP. The purity of synaptosome fraction was validated with western blot and electron microscopy, and the protein abundance alterations were analyzed by mass spectrometry. We observed that SD and RP have a wide impact on neurotransmitter-related proteins at both the presynaptic and postsynaptic membranes. The abundance of synaptic proteins has changed to a greater extent in consequence of SD than during RP: we identified 78 proteins with altered abundance after SD and 39 proteins after the course of RP. Levels of most of the altered proteins were upregulated during SD, while RP showed the opposite tendency, and three proteins (Gabbr1, Anks1b, and Decr1) showed abundance changes with opposite direction after SD and RP. The functional cluster analysis revealed that a majority of the altered proteins is related to signal transduction and regulation, synaptic transmission and synaptic assembly, protein and ion transport, and lipid and fatty acid metabolism, while the interaction network analysis revealed several connections between the significantly altered proteins and the molecular processes of synaptic plasticity or sleep. Our proteomic data implies suppression of SNARE-mediated synaptic vesicle exocytosis and impaired endocytic processes after sleep deprivation. Both SD and RP altered GABA neurotransmission and affected protein synthesis, several regulatory processes and signaling pathways, energy homeostatic processes, and metabolic pathways.

Keywords:  Proteomics; Recovery period; Sleep; Sleep deprivation; Synapse; Synaptosome

DOI:  https://doi.org/10.1007/s12035-021-02699-x
Mol Cell Proteomics. 2021 Dec 31. pii: S1535-9476(21)00164-X. [Epub ahead of print] 100192

Multidimensional dynamics of the proteome in the neurodegenerative and aging mammalian brain.

Byron Andrews, Alan E Murphy, Michele Stofella, Sarah Maslen, Leonardo Almeida-Souza, J Mark Skehel, Nathan G Skene, Frank Sobott, René A W Frank.

  The amount of any given protein in the brain is determined by the rates of its synthesis and destruction, which are regulated by different cellular mechanisms. Here, we combine metabolic labelling in live mice with global proteomic profiling to simultaneously quantify both the flux and amount of proteins in mouse models of neurodegeneration. In multiple models, protein turnover increases were associated with increasing pathology. This method distinguishes changes in protein expression mediated by synthesis from those mediated by degradation. In the AppNL-F knockin mouse model of Alzheimer's disease increased turnover resulted from imbalances in both synthesis and degradation, converging on proteins associated with synaptic vesicle recycling (Dnm1, Cltc, Rims1) and mitochondria (Fis1, Ndufv1). In contrast to disease models, aging in wildtype mice caused a widespread decrease in protein recycling associated with a decrease in autophagic flux. Overall, this simple multidimensional approach enables the comprehensive mapping of proteome dynamics and identifies affected proteins in mouse models of disease and other live animal test settings.

Keywords:  Alzheimer's disease; Protein turnover; Proteomics; SILAM; neurodegeneration

DOI:  https://doi.org/10.1016/j.mcpro.2021.100192
J Integr Neurosci. 2021 Dec 30. 20(4): 895-903

Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via the ABCA1 transmembrane transport system in APP/PS1 double transgenic mice.

Mingyuan Tian, Fanlin Zhou, Zhipeng Teng, Chen Wang, Xiong Zhang, Yangyang Wang, Yu Li.

  The disorder of lipid metabolism, especially cholesterol metabolism, can promote Alzheimer's Disease. Curcumin can ameliorate lipid metabolic disorder in the brain of Alzheimer's Disease patients, while the mechanism is not clear. APP/PS1 (APPswe/PSEN1dE9) double transgenic mice were divided into dementia, low-dose, and high-dose groups and then fed for six months with different dietary concentrations of curcumin. Morris water maze was used to evaluate the transgenic mice's special cognitive and memory ability in each group. In contrast, the cholesterol oxidase-colorimetric method was used to measure total serum cholesterol and high-density lipoprotein levels. Immunohistochemistry was used to evaluate the expression of liver X receptor-β, ATP binding cassette A1 and apolipoprotein A1 of the hippocampus and Aβ42 in the brains of transgenic mice. The mRNA and protein expression levels of liver X receptor-β, retinoid X receptor-α and ATP binding cassette A1 were evaluated using qRT-PCR and Western blotting, respectively. Curcumin improved the special cognitive and memory ability of transgenic Alzheimer's Disease Mice. The total serum cholesterol decreased in Alzheimer's Disease mice fed the curcumin diet, while the high-density lipoprotein increased. The curcumin diet was associated with reduced expression of Aβ and increased expression of liver X receptor-β, ATP binding cassette A1, and apolipoprotein A1 in the CA1 region of the hippocampus. The mRNA and protein levels of retinoid X receptor-α, liver X receptor-β, and ATP binding cassette A1 were higher in the brains of Alzheimer's Disease mice fed the curcumin diet. Our results point to the mechanism by which curcumin improves lipid metabolic disorders in Alzheimer's Disease via the ATP binding cassette A1 transmembrane transport system.

Keywords:  ATP binding cassette A1; Alzheimer's disease; Cholesterol metabolism; Curcumin; Transmembrane transport system

DOI:  https://doi.org/10.31083/j.jin2004091
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Dec 30. pii: S0278-5846(21)00267-0. [Epub ahead of print]115 110508

Early-life stress induces emotional and molecular alterations in female mice that are partially reversed by cannabidiol.

Ana Martín-Sánchez, Héctor González-Pardo, Laia Alegre-Zurano, Adriana Castro-Zavala, Isabel López-Taboada, Olga Valverde, Nélida M Conejo.

  Gender is considered as a pivotal determinant of mental health. Indeed, several psychiatric disorders such as anxiety and depression are more common and persistent in women than in men. In the past two decades, impaired brain energy metabolism has been highlighted as a risk factor for the development of these psychiatric disorders. However, comprehensive behavioural and neurobiological studies in brain regions relevant to anxiety and depression symptomatology are scarce. In the present study, we summarize findings describing cannabidiol effects on anxiety and depression in maternally separated female mice as a well-established rodent model of early-life stress associated with many mental disorders. Our results indicate that cannabidiol could prevent anxiolytic- and depressive-related behaviour in early-life stressed female mice. Additionally, maternal separation with early weaning (MSEW) caused long-term changes in brain oxidative metabolism in both nucleus accumbens and amygdalar complex measured by cytochrome c oxidase quantitative histochemistry. However, cannabidiol treatment could not revert brain oxidative metabolism impairment. Moreover, we identified hyperphosphorylation of mTOR and ERK 1/2 proteins in the amygdala but not in the striatum, that could also reflect altered brain intracellular signalling related with to bioenergetic impairment. Altogether, our study supports the hypothesis that MSEW induces profound long-lasting molecular changes in mTOR signalling and brain energy metabolism related to depressive-like and anxiety-like behaviours in female mice, which were partially ameliorated by CBD administration.

Keywords:  Cannabidiol; Cytochrome c oxidase; ERK 1/2; Early life stress; Maternal separation; mTOR

DOI:  https://doi.org/10.1016/j.pnpbp.2021.110508
Theranostics. 2022 ;12(2): 603-619

HDAC6 inhibition reverses long-term doxorubicin-induced cognitive dysfunction by restoring microglia homeostasis and synaptic integrity.

Blake R McAlpin, Rajasekaran Mahalingam, Anand K Singh, Shruti Dharmaraj, Taylor T Chrisikos, Nabila Boukelmoune, Annemieke Kavelaars, Cobi J Heijnen.

  Breast cancer is the most common female malignancy in both the developed and developing world. Doxorubicin is one of the most commonly used chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed and executive function. Currently, no therapeutic standard for treating CICD exists. Here, we hypothesized that treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor can successfully reverse long-term doxorubicin-induced cognitive dysfunction. Methods: The puzzle box test and novel object/place recognition test were used to assess cognitive function following a therapeutic doxorubicin dosing schedule in female mice. Mitochondrial function and morphology in neuronal synaptosomes were evaluated using the Seahorse XF24 extracellular flux analyzer and transmission electron microscopy, respectively. Hippocampal postsynaptic integrity was evaluated using immunofluorescence. Hippocampal microglia phenotype was determined using advanced imaging techniques and single-nucleus RNA sequencing. Results: A 14-day treatment with a blood-brain barrier permeable HDAC6 inhibitor successfully reversed long-term CICD in the domains of executive function, working and spatial memory. No significant changes in mitochondrial function or morphology in neuronal synaptosomes were detected. Long-term CICD was associated with a decreased expression of postsynaptic PSD95 in the hippocampus. These changes were associated with decreased microglial ramification and alterations in the microglia transcriptome that suggest a stage 1 disease-associated microglia (DAM) phenotype. HDAC6 inhibition completely reversed these doxorubicin-induced alterations, indicating a restoration of microglial homeostasis. Conclusion: Our results show that decreased postsynaptic integrity and a neurodegenerative microglia phenotype closely resembling stage 1 DAM microglia contribute to long-term CICD. Moreover, HDAC6 inhibition shows promise as an efficacious pharmaceutical intervention to alleviate CICD and improve quality of life of breast cancer survivors.

Keywords:  HDAC6 inhibition; chemobrain; chemotherapy-induced cognitive dysfunction; microglia; single-nucleus RNA sequencing

DOI:  https://doi.org/10.7150/thno.67410
Oxid Med Cell Longev. 2021 ;2021 9800794

Hepcidin Promoted Ferroptosis through Iron Metabolism which Is Associated with DMT1 Signaling Activation in Early Brain Injury following Subarachnoid Hemorrhage.

Hongxia Zhang, Robert Ostrowski, Dengzhi Jiang, Qing Zhao, Yidan Liang, Xudong Che, Jun Zhao, Xiang Xiang, Wang Qin, Zhaohui He.

Iron metabolism disturbances play an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH), and hepcidin largely influences iron metabolism. Importantly, iron metabolism may be associated with ferroptosis, recently a nonapoptotic iron-dependent form of cell death that may have a great impact on brain injury after SAH. We investigated hepcidin on iron metabolism and ferroptosis involving divalent metal transporter 1 (DMT1), and ferroportin-1 (FPN1) in a rat model of SAH. Male Sprague-Dawley rats were subjected to the endovascular perforation to induce SAH, and treated with heparin (inhibitor of hepcidin), or oncostatin M (OSM, inducer of hepcidin), or ebselen (inhibitor of DMT1) by intracerebroventricular injections. Hepcidin, DMT1, FPN1 and glutathione peroxidase 4 (GPX4), were detected by western blot and immunofluorescence. Iron metabolism was detected through Perl's iron staining and iron content assay. Ferroptosis, the ROS production, lipid peroxidation (LPO) was evaluated by monitoring methane dicarboxylic aldehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPX4) activity, and transmission electron microscopy. Neurological deficit scores, Evans blue staining and brain water content were also determined to detect EBI 72 h after SAH. Our results showed that inhibition of DMT1 by ebselen could suppress iron accumulation and lipid peroxidation, and thereby alleviate ferroptosis and EBI in SAH rats. Heparin downregulated the expression of hepcidin and DMT1, increased FPN1, and exerted protective effects that were equivalent to those of ebselen on ferroptosis and EBI. In addition, OSM increased the expression of hepcidin and DMT1, decreased FPN1, and aggravated ferroptosis and EBI, while the effect on ferroptosis was reversed by ebselen. Therefore, the study revealed that hepcidin could regulate iron metabolism and contribute to ferroptosis via DMT1 signaling activation in rats with EBI after SAH.

DOI: https://doi.org/10.1155/2021/9800794
iScience. 2022 Jan 21. 25(1): 103551

16pdel lipid changes in iPSC-derived neurons and function of FAM57B in lipid metabolism and synaptogenesis.

Danielle L Tomasello, Jiyoon L Kim, Yara Khodour, Jasmine M McCammon, Maya Mitalipova, Rudolf Jaenisch, Anthony H Futerman, Hazel Sive.

  The complex 16p11.2 deletion syndrome (16pdel) is accompanied by neurological disorders, including epilepsy, autism spectrum disorder, and intellectual disability. We demonstrated that 16pdel iPSC differentiated neurons from affected people show augmented local field potential activity and altered ceramide-related lipid species relative to unaffected. FAM57B, a poorly characterized gene in the 16p11.2 interval, has emerged as a candidate tied to symptomatology. We found that FAM57B modulates ceramide synthase (CerS) activity, but is not a CerS per se. In FAM57B mutant human neuronal cells and zebrafish brain, composition and levels of sphingolipids and glycerolipids associated with cellular membranes are disrupted. Consistently, we observed aberrant plasma membrane architecture and synaptic protein mislocalization, which were accompanied by depressed brain and behavioral activity. Together, these results suggest that haploinsufficiency of FAM57B contributes to changes in neuronal activity and function in 16pdel syndrome through a crucial role for the gene in lipid metabolism.

Keywords:  Cellular neuroscience; Developmental neuroscience; Molecular neuroscience; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2021.103551
Exp Neurol. 2021 Dec 30. pii: S0014-4886(21)00374-5. [Epub ahead of print] 113966

Astrocytic glycogen mobilization participates in salvianolic acid B-mediated neuroprotection against reperfusion injury after ischemic stroke.

Haiyun Guo, Zhen Zhang, Tingting Gu, Doutong Yu, Yanru Shi, Zejun Gao, Zhongheng Wang, Wenming Liu, Ze Fan, Wugang Hou, Huaning Wang, Yanhui Cai.

  Astrocytic glycogen serves as an important glucose reserve, and its degradation provides extra support for neighboring neurons during energy deficiency. Salvianolic acid B (SAB) exerts a neuroprotective effect on reperfusion insult after cerebrovascular occlusion, but the effect of SAB on astrocytic glycogen and its relationship with neuroprotection are not completely understood. Here, we knocked down astrocyte-specific glycogen phosphorylase (GP, the rate-limiting enzyme in glycogenolysis) in vitro and in vivo and investigated the changes in key enzymes in glycogen metabolism by performing immunoblotting in vitro and immunofluorescence in vivo. Neurobehavioral and morphological assessments were conducted to uncover the outcomes during brain reperfusion. SAB accelerated astrocytic glycogenolysis by upregulating GP activity but not GP expression after reperfusion. Suppression of astrocytic glycogenolysis weakened SAB-mediated neuroprotection against the reperfusion insult. In addition, activation of glycogenolysis by SAB contributed to the survival of astrocytes and surrounding neurons by increasing antioxidant levels in astrocytes. Our data reveal that astrocytic GP represents an important metabolic target in SAB-induced protection against brain damage after cerebrovascular recanalization.

Keywords:  Astrocyte; Glycogen mobilization; Ischemia/reperfusion injury; Neuroprotection; Salvianolic acid B

DOI:  https://doi.org/10.1016/j.expneurol.2021.113966
Biol Trace Elem Res. 2022 Jan 04.

Centella asiatica Alleviates AlCl3-induced Cognitive Impairment, Oxidative Stress, and Neurodegeneration by Modulating Cholinergic Activity and Oxidative Burden in Rat Brain.

Zeba Firdaus, Devendra Kumar, Sushil Kumar Singh, Tryambak Deo Singh.

  Aluminum (Al) is linked to the development of many neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, and autism. Centella asiatica (CA) is a regenerating herb traditionally used to stimulate memory. This study was designed to assess the neuroprotective role of ethanolic extract of CA (CAE) in AlCl3-induced neurological conditions in rats. Adult rats were chronically treated with AlCl3 (100 mg/kg b.w./day) for 60 days to establish the dementia model, and co-administration of CAE was evaluated for its ability to attenuate the toxic effect of AlCl3. CAE was given orally at a dose of 150 and 300 mg/kg b.w./day, for 60 days. The behavioral performances of rats were tested through Y-maze and open field tests. Lipid peroxidation, superoxide dismutase, and catalase activity were evaluated to measure oxidative stress; and acetylcholinesterase (AChE) activity was assessed to evaluate cholinergic dysfunction in the rat brain. H&E staining was used to assess structural abnormalities in the cortex and hippocampus. The result showed that AlCl3 induces cognitive dysfunction (impaired learning and memory, anxiety, diminished locomotor activity), oxidative stress, cholinergic impairment, and histopathological alteration in the rat brain. Co-administration of CAE with AlCl3 markedly protects the brain from AlCl3-induced cognitive dysfunction, oxidative stress, AChE activity, and cytoarchitectural alterations. Furthermore, 15 days CAE treatment after 45 days AlCl3 administration markedly ameliorates the AlCl3-induced neurotoxicity indicating its potential for therapeutic use.

Keywords:  Aluminum chloride (AlCl3); Centella asiatica; Cognitive dysfunction; H&E staining; Neurodegeneration; Oxidative stress

DOI:  https://doi.org/10.1007/s12011-021-03083-5
Eur Rev Med Pharmacol Sci. 2021 Dec;pii: 27613. [Epub ahead of print]25(24): 7668-7678

The protective effect of Metformin/Donepezil in diabetic mice brain: evidence from bioinformatics analysis and experiments.

Y Hou, F-Z Li.

OBJECTIVE: To identify candidate differentially expressed genes (DEGs) and pathways in diabetic mice brain with metformin/donepezil, network pharmacology analysis was used and verified by experiments.
MATERIALS AND METHODS: We analyzed GSE62013 microarray datasets derived from the Gene Expression Omnibus (GEO) database for diabetic brain. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database. Subsequently, the protein-protein interaction network (PPI) and Cytoscape were used for visualizing the most significant module and hub genes. Metformin/donepezil were used to treat streptozotocin (STZ)-induced diabetic mice models. Blood glucose levels and Morris water maze test were measured. The apoptotic rate of diabetic brain tissue was analyzed using Annexin V/propidium iodide double staining. The levels of PI3K and AKT in the mice brain tissues were detected by Western blot.
RESULTS: DEGs included 214 up-regulated genes and 100 down-regulated genes in diabetic brain tissues of mice. The enriched GO functions were multicellular organism development, negative regulation of transcription from RNA polymerase II promoter, and extracellular region. The enriched pathways were PI3K-Akt signaling pathway, Linoleic acid metabolism and Arachidonic acid metabolism. Blood glucose levels and apoptosis were reduced in STZ-induced diabetic mice following metformin/donepezil treatment. Metformin/donepezil could reverse this neurocognitive deficiency. Protein levels of PI3K and AKT were significantly increased in STZ-induced diabetic mice.
CONCLUSIONS: Overall, we proposed that 10 genes (Cdc20, Fbxo32, Igtp, Atg7, Fbxo15, Trim37, Psmb8, Ifi47, Asb12, and Asb5) that might be novel hub genes strongly associated with diabetic mice brain. Metformin/donepezil ameliorates STZ-induced brain injury by activating the PI3K/AKT pathway and alleviating apoptosis.

DOI: https://doi.org/10.26355/eurrev_202112_27613
Immunity. 2021 Dec 24. pii: S1074-7613(21)00534-3. [Epub ahead of print]

Disruption of the IL-33-ST2-AKT signaling axis impairs neurodevelopment by inhibiting microglial metabolic adaptation and phagocytic function.

Danyang He, Heping Xu, Huiyuan Zhang, Ruihan Tang, Yangning Lan, Ruxiao Xing, Shaomin Li, Elena Christian, Yu Hou, Paul Lorello, Barbara Caldarone, Jiarui Ding, Lan Nguyen, Danielle Dionne, Pratiksha Thakore, Alexandra Schnell, Jun R Huh, Orit Rozenblatt-Rosen, Aviv Regev, Vijay K Kuchroo.

  To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.

Keywords:  IL-33; bioenergenetics; microglia; neurodevelopment; phagocytosis; seizure; synapse

DOI:  https://doi.org/10.1016/j.immuni.2021.12.001
Neurochem Res. 2022 Jan 04.

Downregulation of Bdnf Expression in Adult Mice Causes Body Weight Gain.

Toru Suzuki, Kenji F Tanaka.

  Gain or loss of appetite and resulting body weight changes are commonly observed in major depressive disorders (MDDs). Brain-derived neurotrophic factor (BDNF) is broadly expressed in the brain and is thought to play a role in the pathophysiology of MDDs and obesity. Congenital loss of function of BDNF causes weight gain in both humans and rodents; however, it is not clear whether acquired loss of function of BDNF also affects body weight. Thus, we exploited mutant mice in which the Bdnf expression level is regulated by the tetracycline-dependent transcriptional silencer (tTS)-tetracycline operator sequence (tetO) system. Time-controlled Bdnf expression using this system allowed us to establish congenital and acquired loss of function of Bdnf in mice. We demonstrated that changes in Bdnf expression influenced body weight during not only the developmental stage but also the adult stage of mice. Although it is still unclear whether acquired Bdnf loss of function in rodents mimics the pathology of MDD, our findings may bridge the mechanistic gap between MDDs and body weight gain in line with BDNF dysfunction.

Keywords:  Bdnf isoforms; Body weight gain; Doxycycline; Isoform-specific Bdnf loss-of-function; Tetracycline-controlled transcriptional silencer; Time-controlled Bdnf loss-of-function

DOI:  https://doi.org/10.1007/s11064-021-03523-7
FEBS J. 2022 Jan 07.

Lipid Metabolism and Alzheimer's Disease: Clinical Evidence, Mechanistic Link and Therapeutic Promise.

Fei Yin.

  Alzheimer's disease (AD) is an age-associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, and a lack of disease-modifying therapeutics. While the abnormal accumulation of lipids was described in the very first report of AD neuropathology, it was not until recent decades that lipid dyshomeostasis became a focus of AD research. Clinically, lipidomic and metabolomic studies have consistently shown alterations in the levels of various lipid classes emerging in early stages of AD brains. Mechanistically, decades of discovery research have revealed multifaceted interactions between lipid metabolism and key AD pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, and myelin degeneration. In the present review, converging evidence defining lipid dyshomeostasis in AD is summarized, followed by discussions on mechanisms by which lipid metabolism contributes to pathogenesis and modifies disease risk. Furthermore, lipid-targeting therapeutic strategies, and the modification of their efficacy by disease stage, ApoE status, and metabolic and vascular profile, are reviewed.

Keywords:  Alzheimer’s Disease; Fatty Acid; Lipid Metabolism; Therapeutics

DOI:  https://doi.org/10.1111/febs.16344
J Physiol Pharmacol. 2021 Aug;72(4):

Ellagic acid prevents streptozotocin-induced hippocampal damage and memory loss in rats by stimulating Nrf2 and nuclear factor-κB, and activating insulin receptor substrate/PI3K/Akt axis.

N A Alfaris, G M Alshammari, J Z Altamimi, D H Aljabryn, R I Alagal, H Aldera, M A Alkhateeb, M A Yahya.

This study examined the protective effect of ellagic acid (EA) against streptozotocin (STZ)-induced hippocampal damage and memory loss and investigated some mechanisms of action. Adult male rats were divided into 4 groups (n = 12) as control, control + EA (50 mg/kg), STZ-DM, and STZ-DM + EA. Treatments were given orally and daily for 8 weeks. Memory function was assessed by the Morris water maze (MWM) and passive learning avoidance test. In addition, blood samples were used to measure glucose and insulin levels. Also, the hippocampus was used to measure markers of oxidative stress, inflammation, and insulin signaling. Associated with the improved memory, EA preserved the structure of the CA1 area of rats' hippocampus and suppressed the hippocampal expression of Bax and cleaved caspase 3. Concomitantly, EA increased rats' weekly weights gain and fasting plasma insulin levels and reduced the hippocampal levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and plasma glucose levels in diabetic rats. In both the control and STZ-DM rats, EA significantly lowered the hippocampal levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but significantly increased the hippocampal levels of glutathione (GSH) and manganese superoxide dismutase (MnSOD), as well as the nuclear levels of NF-κB and nuclear factor-erythroid 2-related factor (Nrf-2). Besides, and in the hippocampus of both groups, EA increased the phosphorylation of insulin receptor substrate (IRS), PI3K, Akt, GS3Kβ, and CREB, and increased levels of BDNF and Bcl-2. In conclusion, these data suggest that the neuroprotective effect of EA on rats' hippocampus and memory function is associated with upregulation of Nrf2 and Bcl-2, suppression of NF-κB, and activation of CREB and IRS/PI3K/Akt/ GS3Kβ axis.

DOI: https://doi.org/10.26402/jpp.2021.4.02
Ecotoxicol Environ Saf. 2021 Dec 31. pii: S0147-6513(21)01239-2. [Epub ahead of print]230 113127

Puerarin alleviates cadmium-induced mitochondrial mass decrease by inhibiting PINK1-Parkin and Nix-mediated mitophagy in rat cortical neurons.

Shuangquan Wen, Li Wang, Tao Wang, Mingchang Xu, Wenhua Zhang, Ruilong Song, Hui Zou, Jianhong Gu, Jianchun Bian, Yan Yuan, Zongping Liu.

  Cadmium (Cd) has well-known central nervous system toxicity, and mitochondria are direct targets of Cd-induced neuronal toxicity. However, how Cd induces mitochondrial mass decrease in terms of its neurotoxic effects remains unknown. Puerarin, an isoflavone extracted from kudzu root, can cross the blood-brain barrier and exert protective effects in nervous system disease. The purpose of the study was to determine the mechanism of Cd-induced mitochondrial mass decrease and the protective role of puerarin in rat cortical neurons. The results indicated that Cd induced mitochondrial mass decrease by activating mitophagy mediated by the PTEN-induced putative kinase protein 1 (PINK1)-E3 ubiquitin ligase (Parkin) and Nip3-like protein X (Nix) pathways in rat cortical neurons. Puerarin improved the Cd-induced decrease in mitochondrial membrane potential (MMP) in vitro, and blocked PINK1-Parkin and Nix-mediated mitophagy, inhibiting Cd-induced mitochondrial mass decrease in rat cortical neurons in vitro and in vivo. In summary, our data clearly indicated that puerarin protects rat cortical neurons against Cd-induced neurotoxicity by ameliorating mitochondrial damage, inhibiting mitophagy-mediated mitochondrial mass decrease. Puerarin appears to have great potential as a neuroprotective agent.

Keywords:  Cadmium; Mitochondrial mass; Mitophagy; Neuron; Puerarin

DOI:  https://doi.org/10.1016/j.ecoenv.2021.113127
Med Sci Monit. 2022 Jan 04. 28 e933978

Activation of α7 Nicotinic Acetylcholine Receptor by its Selective Agonist Improved Learning and Memory of Amyloid Precursor Protein/Presenilin 1 (APP/PS1) Mice via the Nrf2/HO-1 Pathway.

Kun Cao, Jie Xiang, Yang-Ting Dong, Yi Xu, Zhi-Zhong Guan.

BACKGROUND To reveal the mechanism underlying the effect of alpha7 nicotinic acetylcholine receptor (nAChR) on neurodegeneration in Alzheimer disease (AD), the influence of the receptor on recognition in APP/PS1 mice was evaluated by using its selective agonist (PNU-282987). MATERIAL AND METHODS APP/PS1 and wild-type (WT) mice were treated with PNU or saline, respectively, for 7 days at the ages of 6 and 10 months. RESULTS Morris water maze analysis showed that both at 6 and 10 months of age, PNU treatment enhanced the learning and memory of APP/PS1 mice. However, PNU treatment did not alter the number of senile plaques. Furthermore, a higher protein expression of Nrf2/HO-1, ADAM10, SYP, and SNAP-25, and a lower level of oxidative stress, were observed in the hippocampus of APP/PS1 mice treated with PNU compared with the control group. CONCLUSIONS The results indicated that the activation of alpha7 nAChR by PNU improved the learning and memory of mice carrying the APP/PS1 mutation, regulated the levels of enzymes that mediate APP metabolization to reduce ß-amyloid peptide damage, and decreased the level of oxidative stress and maintained synaptic plasticity, in which the mechanism might be enhancement of the Nrf2/HO-1 pathway.

DOI: https://doi.org/10.12659/MSM.933978
J Cell Sci. 2022 Jan 04. pii: jcs.258687. [Epub ahead of print]

Isoform-dependent lysosomal degradation and internalization of Apolipoprotein E requires autophagy proteins.

Gianna M Fote, Nicolette R Geller, Nikolaos Efstathiou, Nathan Hendricks, Demetrios G Vavvas, Jack C Reidling, Leslie M Thompson, Joan S Steffan.

  The human Apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found in cells stably expressing each APOE isoform that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-golgi compartment is degraded by autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that may contribute to AD pathogenesis.

Keywords:  APOE; APOE4; Alzheimer's disease; Chaperone-mediated autophagy; LC3-associated endocytosis

DOI:  https://doi.org/10.1242/jcs.258687
J Diabetes Investig. 2022 Jan 06.

Neuronal regulation of glucagon secretion and gluconeogenesis.

Bernard Thorens.

Hypoglycemia almost never develops in healthy individuals because multiple hypoglycemia sensing systems, located in the periphery and in the central nervous system trigger a coordinated counterregulatory hormonal response to restore normoglycemia. This involves not only the secretion of glucagon but also of epinephrine, norepinephrine, cortisol and growth hormone. Increased hepatic glucose production is also stimulated by direct autonomous nervous connections to the liver that stimulate glycogenolysis and gluconeogenesis. This counterregulatory response, however, becomes deregulated in a significant fraction of diabetic patients that receive insulin therapy. This leads to risk of developing hypoglycemic episodes, of increasing severity, which negatively impact the quality of life of the patients. How hypoglycemia is detected by the central nervous system is being actively investigated. Recent studies using novel molecular biological, optogenetic and chemogenetic techniques, allow the characterization of glucose sensing neurons, the mechanisms of hypoglycemia detection, the neuronal circuits in which they are integrated and the physiological responses they control. This review will discuss recent studies aimed at identifying central hypoglycemia sensing neuronal circuits, how neurons are activated by hypoglycemia, and how they restore normoglycemia.

DOI: https://doi.org/10.1111/jdi.13745
BMC Biol. 2022 Jan 07. 20(1): 12

mtIF3 is locally translated in axons and regulates mitochondrial translation for axonal growth.

Soyeon Lee, Dongkeun Park, Chunghun Lim, Jae-Ick Kim, Kyung-Tai Min.

   BACKGROUND: The establishment and maintenance of functional neural connections relies on appropriate distribution and localization of mitochondria in neurites, as these organelles provide essential energy and metabolites. In particular, mitochondria are transported to axons and support local energy production to maintain energy-demanding neuronal processes including axon branching, growth, and regeneration. Additionally, local protein synthesis is required for structural and functional changes in axons, with nuclear-encoded mitochondrial mRNAs having been found localized in axons. However, it remains unclear whether these mRNAs are locally translated and whether the potential translated mitochondrial proteins are involved in the regulation of mitochondrial functions in axons. Here, we aim to further understand the purpose of such compartmentalization by focusing on the role of mitochondrial initiation factor 3 (mtIF3), whose nuclear-encoded transcripts have been shown to be present in axonal growth cones.
RESULTS: We demonstrate that brain-derived neurotrophic factor (BDNF) induces local translation of mtIF3 mRNA in axonal growth cones. Subsequently, mtIF3 protein is translocated into axonal mitochondria and promotes mitochondrial translation as assessed by our newly developed bimolecular fluorescence complementation sensor for the assembly of mitochondrial ribosomes. We further show that BDNF-induced axonal growth requires mtIF3-dependent mitochondrial translation in distal axons.
CONCLUSION: We describe a previously unknown function of mitochondrial initiation factor 3 (mtIF3) in axonal protein synthesis and development. These findings provide insight into the way neurons adaptively control mitochondrial physiology and axonal development via local mtIF3 translation.

Keywords:  Axon development; Bimolecular fluorescence complementation; Local translation; Mitochondria; Mitochondrial translation

DOI:  https://doi.org/10.1186/s12915-021-01215-w
Recent Adv Inflamm Allergy Drug Discov. 2022 Jan 05.

Neuroinflammation and Behavioral Deficit in Rotenone-Induced Neurotoxicity in Rats and the Possible Effects of Butanolic Extract of Centaurea Africana.

Sabrina Hadjira, Amira Mansour, Ramdane Seghiri, Ahmed Menad, Fadila Benayache, Samir Benayache, Souad Ameddah.

   BACKGROUND: Many studies have used rotenone (ROT) to create an experimental animal model of Parkinson's disease (PD) because of its ability to induce similar behavioral and motor deficits. PD is the most common age-related motoric neurodegenerative disorder. Neuroinflammation and apoptosis play an important role in the pathogenesis of this disease.
OBJECTIVE: This study investigated the effect of butanolic (n-BuOH) extract of Centaurea africana (200 mg/kg, 16 days) on a ROT-induced neurotoxicity model in male Wistar albino rats.
METHODS: Estimation of Tumor Necrosis Factor (TNF-α) and Nitric Oxide (NO) levels along with the myeloperoxidase (MPO) activity in brains was carried out in order to evaluate neuro-inflammation. Oxidative stress, Caspase 3 activity (apoptosis), and behavioral alterations were also evaluated.
RESULTS: In behavior assessment, using Ludolph Movement Analysis Scale, all ROT treated animals showed a decreased locomotor activity. The mitochondrial dysfunction induced by ROT was expressed by a decreased activity of complex I of the mitochondrial respiratory chain and increased lipid peroxidation and caspase 3. Co-treatment with the n-BuOH extract significantly restored the activity of complex I (65.41%) compared to treatment with ROT alone. The n-BuOH extract also reduced the neuroinflammation in rat brains by reducing MPO activity (75.12%), NO levels (77.43%), and TNF-α (71.48%) compared to the group treated with ROT.
CONCLUSION: The obtained results indicated that C. africana n-BuOH extract exhibited a protective effect in rats.

Keywords:  Rotenone; apoptosis; centaurea africana; n-BuOH extract; neuroinflammation; rats

DOI:  https://doi.org/10.2174/2772270816666220105124730
Front Aging Neurosci. 2021 ;13 785727

Manipulations of Glutathione Metabolism Modulate IP3-Mediated Store-Operated Ca2+ Entry on Astroglioma Cell Line.

Nawfel Mokrane, Yassin Snabi, Thierry Cens, Janique Guiramand, Pierre Charnet, Anaïs Bertaud, Claudine Menard, Matthieu Rousset, Marie-Céleste de Jesus Ferreira, Jean-Baptiste Thibaud, Catherine Cohen-Solal, Michel Vignes, Julien Roussel.

  The regulation of the redox status involves the activation of intracellular pathways as Nrf2 which provides hormetic adaptations against oxidative stress in response to environmental stimuli. In the brain, Nrf2 activation upregulates the formation of glutathione (GSH) which is the primary antioxidant system mainly produced by astrocytes. Astrocytes have also been shown to be themselves the target of oxidative stress. However, how changes in the redox status itself could impact the intracellular Ca2+ homeostasis in astrocytes is not known, although this could be of great help to understand the neuronal damage caused by oxidative stress. Indeed, intracellular Ca2+ changes in astrocytes are crucial for their regulatory actions on neuronal networks. We have manipulated GSH concentration in astroglioma cells with selective inhibitors and activators of the enzymes involved in the GSH cycle and analyzed how this could modify Ca2+ homeostasis. IP3-mediated store-operated calcium entry (SOCE), obtained after store depletion elicited by Gq-linked purinergic P2Y receptors activation, are either sensitized or desensitized, following GSH depletion or increase, respectively. The desensitization may involve decreased expression of the proteins STIM2, Orai1, and Orai3 which support SOCE mechanism. The sensitization process revealed by exposing cells to oxidative stress likely involves the increase in the activity of Calcium Release-Activated Channels (CRAC) and/or in their membrane expression. In addition, we observe that GSH depletion drastically impacts P2Y receptor-mediated changes in membrane currents, as evidenced by large increases in Ca2+-dependent K+ currents. We conclude that changes in the redox status of astrocytes could dramatically modify Ca2+ responses to Gq-linked GPCR activation in both directions, by impacting store-dependent Ca2+-channels, and thus modify cellular excitability under purinergic stimulation.

Keywords:  BSO (l-buthionine-sulfoximine); CRAC channel; GSH (glutathione); GSK 7975A; STIM and Orai; store-operated calcium entry; sulforaphane

DOI:  https://doi.org/10.3389/fnagi.2021.785727
iScience. 2021 Dec 17. 24(12): 103484

Drp1 SUMO/deSUMOylation by Senp5 isoforms influences ER tubulation and mitochondrial dynamics to regulate brain development.

Seiya Yamada, Ayaka Sato, Naotada Ishihara, Hiroki Akiyama, Shin-Ichi Sakakibara.

  Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects mitochondrial morphology probably through controlling Drp1 ubiquitination and tubulation of the endoplasmic reticulum. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post-translational modification, in which deSUMOylation enzyme isoforms competitively regulate mitochondrial dynamics via Drp1 SUMOylation levels, in a tightly controlled process of neuronal differentiation and corticogenesis.

Keywords:  Cellular neuroscience; Molecular neuroscience; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2021.103484
Front Neuroendocrinol. 2022 Jan 04. pii: S0091-3022(21)00076-5. [Epub ahead of print] 100974

The hypothalamic paraventricular nucleus as a central hub for the estrogenic modulation of neuroendocrine function and behavior.

D Grassi, M Marraudino, L M Garcia-Segura, G C Panzica.

  Estradiol and hypothalamic paraventricular nucleus (PVN) help coordinate reproduction with body physiology, growth and metabolism. PVN integrates hormonal and neural signals originating in the periphery, generating an output mediated both by its long-distance neuronal projections, and by a variety of neurohormones produced by its magnocellular and parvocellular neurosecretory cells. Here we review the cyto-and chemo-architecture, the connectivity and function of PVN and the sex-specific regulation exerted by estradiol on PVN neurons and on the expression of neurotransmitters, neuromodulators, neuropeptides and neurohormones in PVN. Classical and non-classical estrogen receptors (ERs) are expressed in neuronal afferents to PVN and in specific PVN interneurons, projecting neurons, neurosecretory neurons and glial cells that are involved in the input-output integration and coordination of neurohormonal signals. Indeed, PVN ERs are known to modulate body homeostatic processes such as autonomic functions, stress response, reproduction, and metabolic control. Finally, the functional implications of the estrogenic modulation of the PVN for body homeostasis are discussed.

Keywords:  Arginine-vasopressin; GPER1; corticotrophin releasing hormone; estrogen receptor alpha; estrogen receptor beta; kisspeptin; oxytocin; thyrotropic releasing hormone

DOI:  https://doi.org/10.1016/j.yfrne.2021.100974
Nat Biomed Eng. 2022 Jan 06.

Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

Chenglong Xie, Xu-Xu Zhuang, Zhangming Niu, Ruixue Ai, Sofie Lautrup, Shuangjia Zheng, Yinghui Jiang, Ruiyu Han, Tanima Sen Gupta, Shuqin Cao, Maria Jose Lagartos-Donate, Cui-Zan Cai, Li-Ming Xie, Domenica Caponio, Wen-Wen Wang, Tomas Schmauck-Medina, Jianying Zhang, He-Ling Wang, Guofeng Lou, Xianglu Xiao, Wenhua Zheng, Konstantinos Palikaras, Guang Yang, Kim A Caldwell, Guy A Caldwell, Han-Ming Shen, Hilde Nilsen, Jia-Hong Lu, Evandro F Fang.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

DOI: https://doi.org/10.1038/s41551-021-00819-5