bims-brabim Biomed News
on Brain bioenergetics and metabolism
Issue of 2021–11–07
forty-one papers selected by
João Victor Cabral-Costa, University of São Paulo
  1. Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate.
  2. Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
  3. Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A.
  4. Astrocyte Reactivity in Alzheimer's Disease: Therapeutic Opportunities to Promote Repair.
  5. Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.
  6. Anthocyanin-rich blueberry extracts and anthocyanin metabolite protocatechuic acid promote autophagy-lysosomal pathway and alleviate neurons damage in in vivo and in vitro models of Alzheimer's disease.
  7. Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice.
  8. Sex Differences in Mitochondrial Function Following a Controlled Cortical Impact Traumatic Brain Injury in Rodents.
  9. Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver.
  10. Lipids as early and minimally invasive biomarkers for Alzheimer disease.
  11. Reduced SOD2 expression does not influence prion disease course or pathology in mice.
  12. Multiple roles of short-chain fatty acids in Alzheimer disease.
  13. Microglia Regulate Neuronal Circuits in Homeostatic and High-Fat Diet-Induced Inflammatory Conditions.
  14. New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria.
  15. The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease.
  16. Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer's Disease.
  17. Brain Exosomes as minuscule information hub for Autism Spectrum Disorder.
  18. Propofol protects hippocampal neurons in sleep-deprived rats by inhibiting mitophagy and autophagy.
  19. Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system.
  20. Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity.
  21. Galectins and Their Ligand Glycoconjugates in the Central Nervous System Under Physiological and Pathological Conditions.
  22. Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.
  23. Resistance exercise improves learning and memory and modulates hippocampal metabolomic profile in aged rats.
  24. Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System.
  25. The neuroprotective effects of Insulin-Like Growth Factor 1 via the Hippo/YAP signaling pathway are mediated by the PI3K/AKT cascade following cerebral ischemia/reperfusion injury.
  26. The Role of Zinc Status on Spatial Memory, Hippocampal Synaptic Plasticity, and Insulin Signaling in icv-STZ-Induced Sporadic Alzheimer's-Like Disease in Rats.
  27. Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites.
  28. Microbes, metabolites and (synaptic) malleability, oh my! The effect of the microbiome on synaptic plasticity.
  29. Functional Roles of Neuronal Nitric Oxide Synthase in Neurodegenerative Diseases and Mood Disorders.
  30. O-GlcNAcase inhibitor has protective effects in intracerebral hemorrhage by suppressing the inflammatory response.
  31. SIRT6 Through the Brain Evolution, Development, and Aging.
  32. Cefazolin Improves Anesthesia and Surgery-Induced Cognitive Impairments by Modulating Blood-Brain Barrier Function, Gut Bacteria and Short Chain Fatty Acids.
  33. Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster.
  34. Deformed wing virus infection affects the neurological function of Apis mellifera by altering extracellular adenosine signaling.
  35. A Pro-inflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol.
  36. Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases.
  37. Gut Feelings: The Microbiota-Gut-Brain Axis on Steroids.
  38. The apolipoprotein receptor LRP3 compromises APP levels.
  39. Hypoxia-Induced Neuroinflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Centella asiatica.
  40. Calpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer's Disease.
  41. Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.
  1. Front Neurosci. 2021 ;15 767560
    Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate.
    Wanxin Chen, Xiaoxia Sun, Libin Zhan, Wen Zhou, Tingting Bi.
      Background and Purpose: Neurodegenerative diseases are associated with metabolic disturbances. Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is an essential component in the process of glucose metabolism, and its deficiency exists in various diseases such as Alzheimer's disease (AD), epilepsy, Leigh's syndrome, and diabetes-associated cognitive decline. However, the exact role of PDHA1 deficiency in neurodegenerative diseases remains to be elucidated. In this study, we explored the effect of PDHA1 deficiency on cognitive function and its molecular mechanism. Methods: A hippocampus-specific Pdha1 knockout (Pdha1 -/-) mouse model was established, and behavioral tests were used to evaluate the cognitive function of mice. Transmission electron microscopy (TEM) was performed to observe the morphological changes of the hippocampus. The lactate level in the hippocampus was measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the possible mechanism of the effect of PDHA1 on cognition. Results: Pdha1 knockout damaged the spatial memory of mice and led to the ultrastructural disorder of hippocampal neurons. Lactate accumulation and abnormal lactate transport occurred in Pdha1 -/- mice, and the cyclic AMP-protein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway was inhibited. Conclusion: Lactate accumulation caused by PDHA1 deficiency in the hippocampus may impair cognitive function by inhibiting the cAMP/PKA/CREB pathway.
    Keywords:  PDHA1; cognitive function; hippocampus; knockout mice; lactate
    DOI:  https://doi.org/10.3389/fnins.2021.767560
  2. Commun Biol. 2021 Nov 04. 4(1): 1262
    Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
    Aine Fairbrother-Browne, Aminah T Ali, Regina H Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten, Alan Hodgkinson.
      Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.
    DOI:  https://doi.org/10.1038/s42003-021-02792-w
  3. Front Cell Neurosci. 2021 ;15 739425
    Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A.
    Tammaryn Lashley, Maria-Armineh Tossounian, Neve Costello Heaven, Samantha Wallworth, Sew Peak-Chew, Aaron Bradshaw, J Mark Cooper, Rohan de Silva, Surjit Kaila Srai, Oksana Malanchuk, Valeriy Filonenko, Margreet B Koopman, Stefan G D Rüdiger, Mark Skehel, Ivan Gout.
      Alzheimer's disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.
    Keywords:  Alzheimer’s disease; Coenzyme A; neurodegeneration; oxidative stress; protein CoAlation; tau
    DOI:  https://doi.org/10.3389/fncel.2021.739425
  4. Curr Alzheimer Res. 2021 Oct 29.
    Astrocyte Reactivity in Alzheimer's Disease: Therapeutic Opportunities to Promote Repair.
    Nazanin Mirzaei, Nicola Davis, Tsz Wing Chau, Magdalena Sastre.
      Astrocytes are fast climbing the ladder of importance in neurodegenerative disorders, particularly in Alzheimer's disease (AD), with the prominent presence of reactive astrocytes sur- rounding amyloid β- plaques, together with activated microglia. Reactive astrogliosis, implying morphological and molecular transformations in astrocytes, seems to precede neurodegeneration, suggesting a role in the development of the disease. Single-cell transcriptomics has recently demon- strated that astrocytes from AD brains are different from "normal" healthy astrocytes, showing dys- regulations in areas such as neurotransmitter recycling, including glutamate and GABA, and im- paired homeostatic functions. However, recent data suggest that the ablation of astrocytes in mouse models of amyloidosis results in an increase in amyloid pathology as well as in the inflammatory profile and reduced synaptic density, indicating that astrocytes mediate neuroprotective effects. The idea that interventions targeting astrocytes may have great potential for AD has therefore emerged, supported by a range of drugs and stem cell transplantation studies that have successfully shown a therapeutic effect in mouse models of AD. In this article, we review the latest reports on the role and profile of astrocytes in AD brains and how manipulation of astrocytes in animal mod- els has paved the way for the use of treatments enhancing astrocytic function as future therapeutic avenues for AD.
    Keywords:  Alzheimer’s disease; amyloid; astrocyte; glial cells
    DOI:  https://doi.org/10.2174/1567205018666211029164106
  5. Neurobiol Dis. 2021 Nov 01. pii: S0969-9961(21)00291-6. [Epub ahead of print] 105542
    Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.
    F Biyong Essi, Tremblay Cyntia, Leclerc Manon, Caron Vicky, Alfos Serge, Helbling Jean-Christophe, Rodriguez Léa, Pernet Vincent, A Bennett David, Pallet Véronique, Calon Frédéric.
       BACKGROUND: Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD.
    METHODS: We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20).
    RESULTS: The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ40 and Aβ42, as well as the phosphorylation of Tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal amyloid load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex.
    CONCLUSION: Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.
    Keywords:  3xTg-AD mouse; Aging; Alzheimer's disease; Amyloid; Diet; Prevention; RXRs; Sex; Vitamin A
    DOI:  https://doi.org/10.1016/j.nbd.2021.105542
  6. Nutrition. 2021 Aug 31. pii: S0899-9007(21)00335-X. [Epub ahead of print]93 111473
    Anthocyanin-rich blueberry extracts and anthocyanin metabolite protocatechuic acid promote autophagy-lysosomal pathway and alleviate neurons damage in in vivo and in vitro models of Alzheimer's disease.
    Hui Li, Tingting Zheng, Fuzhi Lian, Tong Xu, Wenya Yin, Yugang Jiang.
       OBJECTIVES: As the global aging phenomenon intensifies, the incidence of Alzheimer's disease (AD) is gradually increasing. Diet appears to be an effective way to prevent and delay the progression of AD. Previous studies have found that cognitive impairment and neuronal damage were effectively alleviated by blueberry extract (BBE) in AD mice, but its mechanism is still unclear. The aims of this study were to detect the main anthocyanins of BBE; then to verify the protective effects of anthocyanin-rich BBE on hippocampal neurons and the promotion of autophagy; and finally to investigate the main protective effects and mechanisms of protocatechuic acid (PCA), a major metabolite of BBE, for promoting autophagy and thus playing a neuroprotective role.
    METHODS: APP/PS1 mice were given 150 mg/kg BBE daily for 16 wk. Morphology of neurons was observed and autophagy-related proteins were detected.
    RESULTS: Neuron damage in morphology was reduced and the expression of autophagy-related proteins in APP/PS1 mice were promoted after BBE treatment. In vitro, Aβ25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and reactive oxygen species, was effectively reversed by PCA. Furthermore, by adding autophagy inducers rapamycin and autophagy inhibitors Bafilomycin A1, it was verified that degradation of autophagosomes was upregulated and autophagy was promoted by PCA.
    CONCLUSION: This study elucidated the mechanism of BBE for reducing neuronal damage by promoting neuronal autophagy and proved PCA may be the main bioactive metabolite of BBE for neuroprotective effects, providing a basis for dietary intervention in AD.
    Keywords:  Alzheimer's disease (AD); Autophagy; Aβ(25-35); Primary neuron; Protocatechuic acid (PCA); blueberry extract (BBE)
    DOI:  https://doi.org/10.1016/j.nut.2021.111473
  7. Exp Biol Med (Maywood). 2021 Nov 02. 15353702211056866
    Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice.
    Natalia V Bobkova, Daria Y Zhdanova, Natalia V Belosludtseva, Nikita V Penkov, Galina D Mironova.
      Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer's type degeneration. Control OBX mice demonstrated loss of spatial memory tested in the Morris water maze. Immunocytochemical analysis revealed that allogeneic mitochondria colocalized with the markers of astrocytes and neurons in hippocampal cell culture. The results suggest that a non-invasive route intranasal administration of mitochondria may be a promising approach to the treatment of neurodegenerative diseases characterized, like Alzheimer's disease, by mitochondrial dysfunction.
    Keywords:  Mitochondrial therapy; intranasal microinjections; mitochondrial dysfunction; neurodegenerative diseases; olfactory bulbectomized mice; spatial memory
    DOI:  https://doi.org/10.1177/15353702211056866
  8. Front Mol Neurosci. 2021 ;14 753946
    Sex Differences in Mitochondrial Function Following a Controlled Cortical Impact Traumatic Brain Injury in Rodents.
    Olivia J Kalimon, Patrick G Sullivan.
      Traumatic brain injury (TBI) is a complex disease to study due to the multifactorial injury cascades occurring after the initial blow to the head. One of the most vital players in this secondary injury cascade, and therapeutic target of interest, is the mitochondrion. Mitochondria are important for the generation of cellular energy, regulation of cell death, and modulation of intracellular calcium which leaves these "powerhouses" especially susceptible to damage and dysfunction following traumatic brain injury. Most of the existing studies involving mitochondrial dysfunction after TBI have been performed in male rodent models, leaving a gap in knowledge on these same outcomes in females. This mini-review intends to highlight the available data on mitochondrial dysfunction in male and female rodents after controlled cortical impact (CCI) as a common model of TBI.
    Keywords:  CNS injury; bioenergetics; glucose utilization; oxidative stress; sex hormone influence
    DOI:  https://doi.org/10.3389/fnmol.2021.753946
  9. Front Pharmacol. 2021 ;12 724471
    Hepatic Ischemia-Reperfusion Impairs Blood-Brain Barrier Partly Due to Release of Arginase From Injured Liver.
    Liang Zhu, Han Zhou, Feng Xu, Hanyu Yang, Ping Li, Yun Sheng, Peihua Liu, Weimin Kong, Xiaonan Liu, Lu Yang, Li Liu, Xiaodong Liu.
      Aim: Hepatic ischemia-reperfusion (HIR) induces remote organs injury, including the brain. The homeostasis of the brain is maintained by the blood-brain barrier (BBB); thus, we aimed to investigate whether HIR impaired BBB and attempted to elucidate its underlying mechanism. Methods: Cell viability of human cerebral microvascular endothelial cells (hCMEC/D3) was measured following 24 h incubation with a serum of HIR rat undergoing 1 h ischemia and 4 h reperfusion, liver homogenate, or lysate of primary hepatocytes of the rat. The liver homogenate was precipitated using (NH4)2SO4 followed by separation on three columns and electrophoresis to identify the toxic molecule. Cell activity, apoptosis, proliferation, cell cycle, and expressions of proteins related to cell cycle were measured in hCMEC/D3 cells incubated with identified toxic molecules. HIR rats undergoing 1 h ischemia and 24 h reperfusion were developed to determine the release of an identified toxic molecule. BBB function was indexed as permeability to fluorescein and brain water. Endothelial cell proliferation and expressions of proteins related to the cell cycle in cerebral microvessels were measured by immunofluorescence and western blot. Results: Toxic molecule to BBB in the liver was identified to be arginase. Arginase inhibitor nor-NOHA efficiently attenuated hCMEC/D3 damage caused by liver homogenate and serum of HIR rats. Both arginase and serum of HIR rats significantly lowered arginine (Arg) in the culture medium. Arg addition efficiently attenuated the impairment of hCMEC/D3 caused by arginase or Arg deficiency, demonstrating that arginase impaired hCMEC/D3 via depriving Arg. Both arginase and Arg deficiency damaged hCMEC/D3 cells by inhibiting cell proliferation, retarding the cell cycle to G1 phase, and downregulating expressions of cyclin A, cyclin D, CDK2, and CDK4. HIR notably increased plasma arginase activity and lowered Arg level, increased the BBB permeability accompanied with enhanced brain water, and decreased the proliferative cells (marked by Ki67) in cerebral microvessels (marked by CD31) and protein expressions of cyclin A, cyclin D, CDK2 and CDK4 in isolated brain microvessels. Oral supplement of Arg remarkably attenuated these HIR-induced alterations. Conclusion: HIR leads to substantial release of arginase from the injured liver and then deprives systemic Arg. The Arg deficiency further impairs BBB via inhibiting the proliferation of brain microvascular endothelial cells by cell cycle arrest.
    Keywords:  arginase; arginine deficiency; blood-brain barrier; cell cycle; cell proliferation; hepatic ischemia-reperfusion
    DOI:  https://doi.org/10.3389/fphar.2021.724471
  10. Curr Neuropharmacol. 2021 Nov 02.
    Lipids as early and minimally invasive biomarkers for Alzheimer disease.
    Esther Casas-Fernández, Carmen Peña-Bautista, Miguel Baquero, Consuelo Cháfer-Pericás.
      Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Specifically, typical late-onset AD is a sporadic form with a complex etiology that affects over 90% of patients. The current gold standard for AD diagnosis is based on the determination of amyloid status by the analysis of cerebrospinal fluid samples or by brain positron emission tomography. These procedures have some disadvantages to become widely used (expensive, invasive). As alternative, blood metabolites have recently emerged as promising AD biomarkers. Small molecules that cross the compromised AD blood-brain barrier, could be determined in plasma to improve clinical AD diagnosis at early stages through minimally invasive techniques. Specifically, lipids could play an important role in AD since brain has a high lipid content and they are present ubiquitously inside amyloid plaques. Therefore, a systematic review was performed with the aim of identifying blood lipid metabolites as potential early AD biomarkers. In conclusion, some lipid families (fatty acids, glycerolipids, glycerophospholipids, sphingolipids, lipid peroxidation compounds) showed impaired levels at early AD stages. Ceramide levels were significantly higher in AD subjects and polyunsaturated fatty acids levels were significantly lower in AD. Also, high arachidonic acid levels were found in AD patients in contrast to low sphingomyelin levels. Consequently, these lipid biomarkers could be used for minimally invasive and early AD clinical diagnosis.
    Keywords:  Alzheimer disease; biomarker; blood; diagnosis; lipid
    DOI:  https://doi.org/10.2174/1570159X19666211102150955
  11. PLoS One. 2021 ;16(11): e0259597
    Reduced SOD2 expression does not influence prion disease course or pathology in mice.
    Simote T Foliaki, Brent Race, Katie Williams, Chase Baune, Bradley R Groveman, Cathryn L Haigh.
      Prion diseases are progressive, neurodegenerative diseases affecting humans and animals. Also known as the transmissible spongiform encephalopathies, for the hallmark spongiform change seen in the brain, these diseases manifest increased oxidative damage early in disease and changes in antioxidant enzymes in terminal brain tissue. Superoxide dismutase 2 (SOD2) is an antioxidant enzyme that is critical for life. SOD2 knock-out mice can only be kept alive for several weeks post-birth and only with antioxidant therapy. However, this results in the development of a spongiform encephalopathy. Consequently, we hypothesized that reduced levels of SOD2 may accelerate prion disease progression and play a critical role in the formation of spongiform change. Using SOD2 heterozygous knock-out and litter mate wild-type controls, we examined neuronal long-term potentiation, disease duration, pathology, and degree of spongiform change in mice infected with three strains of mouse adapted scrapie. No influence of the reduced SOD2 expression was observed in any parameter measured for any strain. We conclude that changes relating to SOD2 during prion disease are most likely secondary to the disease processes causing toxicity and do not influence the development of spongiform pathology.
    DOI:  https://doi.org/10.1371/journal.pone.0259597
  12. Nutrition. 2021 Sep 23. pii: S0899-9007(21)00361-0. [Epub ahead of print]93 111499
    Multiple roles of short-chain fatty acids in Alzheimer disease.
    Hui Chen, Lei Meng, Liang Shen.
      Alzheimer disease (AD) is the most common form of neurodegenerative disease in older adults and has a complicated etiology. Recently, the roles of short-chain fatty acids (SCFAs), the main metabolites generated by fermentation of dietary fiber by gut microbiota, in the pathogenesis of AD have attracted considerable interest. This study analyzed the multiple roles of SCFAs in AD pathogenesis from five aspects, including: 1) epigenetic regulation; 2) modulation of neuroinflammation; 3) maintenance of the blood-brain barrier (BBB); 4) regulation of brain metabolism; and 5) interference in amyloid protein formation. According to the currently available evidence, SCFAs, particularly butyrate, cause important biological effects that interfere with the development of AD. However, the effect of other SCFAs, such as propionate, on AD might be either beneficial or harmful to different pathways, indicating that the role of SCFAs in the pathogenesis of AD is rather complicated and warrants further investigations.
    Keywords:  Alzheimer disease; Gut microbiota; Pathogenesis; Short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.nut.2021.111499
  13. Front Cell Neurosci. 2021 ;15 722028
    Microglia Regulate Neuronal Circuits in Homeostatic and High-Fat Diet-Induced Inflammatory Conditions.
    Xiao-Lan Wang, Lianjian Li.
      Microglia are brain resident macrophages, which actively survey the surrounding microenvironment and promote tissue homeostasis under physiological conditions. During this process, microglia participate in synaptic remodeling, neurogenesis, elimination of unwanted neurons and cellular debris. The complex interplay between microglia and neurons drives the formation of functional neuronal connections and maintains an optimal neural network. However, activation of microglia induced by chronic inflammation increases synaptic phagocytosis and leads to neuronal impairment or death. Microglial dysfunction is implicated in almost all brain diseases and leads to long-lasting functional deficiency, such as hippocampus-related cognitive decline and hypothalamus-associated energy imbalance (i.e., obesity). High-fat diet (HFD) consumption triggers mediobasal hypothalamic microglial activation and inflammation. Moreover, HFD-induced inflammation results in cognitive deficits by triggering hippocampal microglial activation. Here, we have summarized the current knowledge of microglial characteristics and biological functions and also reviewed the molecular mechanism of microglia in shaping neural circuitries mainly related to cognition and energy balance in homeostatic and diet-induced inflammatory conditions.
    Keywords:  cognition; inflammation; microglia; neuronal circuits; obesity; phagocytosis
    DOI:  https://doi.org/10.3389/fncel.2021.722028
  14. Curr Neuropharmacol. 2021 Oct 31.
    New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria.
    Zeyu Zhang, Anke Zhang, Yibo Liu, Xiaoming Hu, Yuanjian Fang, Xiaoyu Wang, Yujie Luo, Cameron Lenahan, Sheng Chen.
      Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes, and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (ΔΨm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets, and summarize the promising therapeutic strategies targeting mitochondria for SAH.
    Keywords:  Apoptosis; Mitophagy; Delayed cerebral ischemia; Early brain injury; Mitochondria; Oxidative stress; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.2174/1570159X19666211101103646
  15. Cureus. 2021 Sep;13(9): e18362
    The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease.
    Amy L Hobday, Mayur S Parmar.
      Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between DM and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles. In DM, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3β (GSK-3β) activity showing to enhance tau phosphorylation. In DM and AD, GSK-3β signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why DM patients have an increased risk of developing AD with disease progression and aging. Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in DM have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between DM and AD as it relates to tau pathology. More understanding of the link between DM and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.
    Keywords:  alzheimer's disease; amyloid beta; endocrinology and diabetes; hyperglycemia; tauopathy
    DOI:  https://doi.org/10.7759/cureus.18362
  16. J Alzheimers Dis. 2021 Oct 25.
    Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer's Disease.
    Angie K Torres, Claudia Jara, Han S Park-Kang, Catalina M Polanco, Diego Tapia, Fabián Alarcón, Adely de la Peña, Jesus Llanquinao, Gabriela Vargas-Mardones, Javiera A Indo, Nibaldo C Inestrosa, Cheril Tapia-Rojas.
      Alzheimer's disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, AβPP could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact with newly formed ones or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.
    Keywords:  Alzheimer’s disease; amyloid-β; amyloid-β protein precursor; cognitive impairment; mitochondria; neurofibrillary tangles; synapses; synaptic mitochondria
    DOI:  https://doi.org/10.3233/JAD-215139
  17. Expert Rev Mol Diagn. 2021 Nov 01.
    Brain Exosomes as minuscule information hub for Autism Spectrum Disorder.
    Deepika Delsa Dean, Sarita Agarwal, Srinivasan Muthuswamy, Ambreen Asim.
       INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder initiating in the first three years of life. Early initiation of management therapies can significantly improve the health and quality of life of ASD subjects. Thus, indicating the need for suitable biomarkers for the early identification of ASD. Various biological domains were investigated in the quest for reliable biomarkers. However, most biomarkers are in the preliminary stage, and clinical validation is yet to be defined. Exosome based research gained momentum in various Central Nervous System disorders for biomarker identification. However, the utility and prospect of exosomes in ASD is still underexplored.
    AREAS COVERED: In the present review, we summarised the biomarker discovery current status and the future of brain-specific exosomes in understanding pathophysiology and its potential as a biomarker. The studies reviewed herein were identified via systematic search (dated: June 2021) of PubMed using variations related to autism (ASD OR autism OR Autism spectrum disorder) AND exosomes AND/OR biomarkers.
    EXPERT OPINION: As exosomess are highly relevant in brain disorders like ASD, direct access to brain tissue for molecular assessment is ethically impossible. Thus investigating the brain-derived exosomes would undoubtedly answer many unsolved aspects of the pathogenesis and provide reliable biomarkers.
    Keywords:  Autism Spectrum Disorder (ASD); Biomarkers; Brain-derived Exosomes; Exosomes; Proteins; miRNA
    DOI:  https://doi.org/10.1080/14737159.2021.2000395
  18. Ann Transl Med. 2021 Sep;9(18): 1427
    Propofol protects hippocampal neurons in sleep-deprived rats by inhibiting mitophagy and autophagy.
    Weixin Dai, Yong Xiao, Youbing Tu, Fei Xiao, Yizhi Lu, Yinying Qin, Yubo Xie.
       Background: Sleep deprivation (SD) causes a disturbance in the cognitive function of rats. While propofol has a powerful sedative and hypnotic effect and is an antioxidant, its effect on the cognitive function of rats following SD remains unknown. The purpose of this study was to explore the protective effects of propofol on excessive autophagy and mitophagy in the hippocampus of rats after SD.
    Methods: Adult male rats were intraperitoneally injected with 30 mg/kg of propofol after 96 hours of SD. Then we evaluated the effect of propofol on the cognitive function of sleep deprived rats by the Morris water maze. Transmission electron microscopy, Western blotting, PCR, immunohistochemistry, autophagy enhancer and autophagy inhibitor were used to study the effect of propofol on hippocampal neurons of rat with excessive autophagy and mitophagy.
    Results: The behavioral experimental results of the Morris water maze showed that propofol improved the learning and memory ability of sleep-deprived rats. The expression of Beclin1, PINK1, parkin, p62, and LC3 protein increased significantly after sleep deprivation. While the intervention of propofol could significantly reduce the expression of these proteins, rapamycin treatment eliminated this effect.
    Conclusions: Our findings showed that propofol could reduce the impairment of learning and memory in sleep-deprived rats by inhibiting excessive autophagy and mitophagy in hippocampal neurons. This strategy may provide an application basis for the clinical use of propofol in patients with chronic insomnia.
    Keywords:  Sleep deprivation (SD); autophagy; cognitive function; mitophagy; propofol
    DOI:  https://doi.org/10.21037/atm-21-3872
  19. Eur J Histochem. 2021 Nov 02. 65(4):
    Distribution of α-synuclein in normal human jejunum and its relations with the chemosensory and neuroendocrine system.
    Arianna Casini, Romina Mancinelli, Caterina Loredana Mammola, Luigi Pannarale, Piero Chirletti, Paolo Onori, Rosa Vaccaro.
      Alpha-synuclein (α-syn) is a presynaptic neuronal protein and its structural alterations play an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). It has been originally described in the brain and aggregated α-syn has also been found in the peripheral nerves including the enteric nervous system (ENS) of PD patients. ENS is a network of neurons and glia found in the gut wall which controls gastrointestinal function independently from the central nervous system. Moreover, two types of epithelial cells are crucial in the creation of an interface between the lumen and the ENS: they are the tuft cells and the enteroendocrine cells (EECs). In addition, the abundant enteric glial cells (EGCs) in the intestinal mucosa play a key role in controlling the intestinal epithelial barrier. Our aim was to localize and characterize the presence of α-syn in the normal human jejunal wall. Surgical specimens of proximal jejunum were collected from patients submitted to pancreaticoduodenectomy and intestinal sections underwent immunohistochemical procedure. Alpha-syn has been found both at the level of ENS and the epithelial cells. To characterize α-syn immunoreactive epithelial cells, we used markers such as choline acetyltransferase (ChAT), useful for the identification of tuft cells. Then we evaluated the co-presence of α-syn with serotonin (5-HT), expressed in EECs. Finally, we used the low-affinity nerve growth factor receptor (p75NTR), to detect peripheral EGCs. The presence of α-syn has been demonstrated in EECs, but not in the tuft cells. Additionally, p75NTR has been highlighted in EECs of the mucosal layer and co-localized with α-syn in EECs but not with ChAT-positive cells. These findings suggest that α-syn could play a possible role in synaptic transmission of the ENS and may contribute to maintain the integrity of the epithelial barrier of the small intestine through EECs.
    DOI:  https://doi.org/10.4081/ejh.2021.3310
  20. World J Psychiatry. 2021 Oct 19. 11(10): 830-840
    Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity.
    Valentina Bashkatova.
      Dopaminergic neurotoxicity is characterized by damage and death of dopaminergic neurons. Parkinson's disease (PD) is a neurodegenerative disorder that primarily involves the loss of dopaminergic neurons in the substantia nigra. Therefore, the study of the mechanisms, as well as the search for new targets for the prevention and treatment of neurodegenerative diseases, is an important focus of modern neuroscience. PD is primarily caused by dysfunction of dopaminergic neurons; however, other neurotransmitter systems are also involved. Research reports have indicated that the glutamatergic system is involved in different pathological conditions, including dopaminergic neurotoxicity. Over the last two decades, the important functional interplay between dopaminergic and glutamatergic systems has stimulated interest in the possible role of metabotropic glutamate receptors (mGluRs) in the development of extrapyramidal disorders. However, the specific mechanisms driving these processes are presently unclear. The participation of the universal neuronal messenger nitric oxide (NO) in the mechanisms of dopaminergic neurotoxicity has attracted increased attention. The current paper aims to review the involvement of mGluRs and the contribution of NO to dopaminergic neurotoxicity. More precisely, we focused on studies conducted on the rotenone-induced PD model. This review is also an outline of our own results obtained using the method of electron paramagnetic resonance, which allows quantitation of NO radicals in brain structures.
    Keywords:  Dopaminergic neurotoxicity; Metabotropic glutamate receptors; Nitric oxide; Parkinson's disease; Rotenone
    DOI:  https://doi.org/10.5498/wjp.v11.i10.830
  21. Front Neuroanat. 2021 ;15 767330
    Galectins and Their Ligand Glycoconjugates in the Central Nervous System Under Physiological and Pathological Conditions.
    Junko Nio-Kobayashi, Tetsuya Itabashi.
      Galectins are β-galactoside-binding lectins consisting of 15 members in mammals. Galectin-1,-3,-4,-8, and -9 are predominantly expressed in the central nervous system (CNS) and regulate various physiological and pathological events. This review summarizes the current knowledge of the cellular expression and role of galectins in the CNS, and discusses their functions in neurite outgrowth, myelination, and neural stem/progenitor cell niches, as well as in ischemic/hypoxic/traumatic injuries and neurodegenerative diseases such as multiple sclerosis. Galectins are expressed in both neurons and glial cells. Galectin-1 is mainly expressed in motoneurons, whereas galectin-3-positive neurons are broadly distributed throughout the brain, especially in the hypothalamus, indicating its function in the regulation of homeostasis, stress response, and the endocrine/autonomic system. Astrocytes predominantly contain galectin-1, and galectin-3 and-9 are upregulated along with its activation. Activated, but not resting, microglia contain galectin-3, supporting its phagocytic activity. Galectin-1,-3, and -4 are characteristically expressed during oligodendrocyte differentiation. Galectin-3 from microglia promotes oligodendrocyte differentiation and myelination, while galectin-1 and axonal galectin-4 suppress its differentiation and myelination. Galectin-1- and- 3-positive cells are involved in neural stem cell niche formation in the subventricular zone and hippocampal dentate gyrus, and the migration of newly generated neurons and glial cells to the olfactory bulb or damaged lesions. In neurodegenerative diseases, galectin-1,-8, and -9 have neuroprotective and anti-inflammatory activities. Galectin-3 facilitates pro-inflammatory action; however, it also plays an important role during the recovery period. Several ligand glycoconjugates have been identified so far such as laminin, integrins, neural cell adhesion molecule L1, sulfatide, neuropilin-1/plexinA4 receptor complex, triggering receptor on myeloid cells 2, and T cell immunoglobulin and mucin domain. N-glycan branching on lymphocytes and oligodendroglial progenitors mediated by β1,6-N-acetylglucosaminyltransferase V (Mgat5/GnTV) influences galectin-binding, modulating inflammatory responses and remyelination in neurodegenerative diseases. De-sulfated galactosaminoglycans such as keratan sulfate are potential ligands for galectins, especially galectin-3, regulating neural regeneration. Galectins have multitudinous functions depending on cell type and context as well as post-translational modifications, including oxidization, phosphorylation, S-nitrosylation, and cleavage, but there should be certain rules in the expression patterns of galectins and their ligand glycoconjugates, possibly related to glucose metabolism in cells.
    Keywords:  Mgat5/GnTV; galectin; glucose metabolism; glycan; keratan sulfate; neurodegenerative disease; post-translational modification
    DOI:  https://doi.org/10.3389/fnana.2021.767330
  22. Mol Neurobiol. 2021 Nov 02.
    Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.
    Rishika Dhapola, Phulen Sarma, Bikash Medhi, Ajay Prakash, Dibbanti HariKrishna Reddy.
      Alzheimer's disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective.
    Keywords:  Alzheimer’s disease; Drugs; Fusion-fission proteins; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1007/s12035-021-02612-6
  23. Neurosci Lett. 2021 Nov 01. pii: S0304-3940(21)00701-1. [Epub ahead of print] 136322
    Resistance exercise improves learning and memory and modulates hippocampal metabolomic profile in aged rats.
    Fernando Tadeu Serra, Fabrizio Dos Santos Cardoso, Nathália Petraconi, Julio Cesar Claudino Dos Santos, Bruno Henrique Silva Araujo, Ricardo Mário Arida, Sérgio Gomes da Silva.
      Physical activity has been considered an important non-medication intervention to preserve mnemonic processes during aging. However, how resistance exercise promotes such benefits remains unclear. A possible hypothesis is that brain-metabolic changes of regions responsible for memory consolidation is affected by muscular training. Therefore, we analyzed the memory, axiety and the metabolomic of aged male Wistar rats (19-20 months old in the 1st day of experiment) submitted to a 12-week resistance exercise protocol (EX, n = 11) or which remained without physical exercise (CTL, n = 13). Barnes maze, elevated plus maze and inhibitory avoidance tests were used to assess the animals' behaviour. The metabolomic profile was identified by nuclear magnetic resonance spectrometry. EX group had better performance in the tests of learning and spatial memory in Barnes maze, and an increase of short and long-term aversive memories formation in inhibitory avoidance. In addition, the exercised animals showed a greater amount of metabolites, such as 4-aminobutyrate, acetate, butyrate, choline, fumarate, glycerol, glycine, histidine, hypoxanthine, isoleucine, leucine, lysine, niacinamide, phenylalanine, succinate, tyrosine, valine and a reduction of ascorbate and aspartate compared to the control animals. These data indicate that the improvement in learning and memory of aged rats submitted to resistance exercise program is associated by changes in the hippocampal metabolomic profile.
    Keywords:  aging; brain; cognition; hippocampus; metabolomic; resistance exercise training
    DOI:  https://doi.org/10.1016/j.neulet.2021.136322
  24. Front Cell Neurosci. 2021 ;15 748849
    Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System.
    Davide Marangon, Nicolò Caporale, Marta Boccazzi, Maria P Abbracchio, Giuseppe Testa, Davide Lecca.
      Myelin is the lipidic insulating structure enwrapping axons and allowing fast saltatory nerve conduction. In the central nervous system, myelin sheath is the result of the complex packaging of multilamellar extensions of oligodendrocyte (OL) membranes. Before reaching myelinating capabilities, OLs undergo a very precise program of differentiation and maturation that starts from OL precursor cells (OPCs). In the last 20 years, the biology of OPCs and their behavior under pathological conditions have been studied through several experimental models. When co-cultured with neurons, OPCs undergo terminal maturation and produce myelin tracts around axons, allowing to investigate myelination in response to exogenous stimuli in a very simple in vitro system. On the other hand, in vivo models more closely reproducing some of the features of human pathophysiology enabled to assess the consequences of demyelination and the molecular mechanisms of remyelination, and they are often used to validate the effect of pharmacological agents. However, they are very complex, and not suitable for large scale drug discovery screening. Recent advances in cell reprogramming, biophysics and bioengineering have allowed impressive improvements in the methodological approaches to study brain physiology and myelination. Rat and mouse OPCs can be replaced by human OPCs obtained by induced pluripotent stem cells (iPSCs) derived from healthy or diseased individuals, thus offering unprecedented possibilities for personalized disease modeling and treatment. OPCs and neural cells can be also artificially assembled, using 3D-printed culture chambers and biomaterial scaffolds, which allow modeling cell-to-cell interactions in a highly controlled manner. Interestingly, scaffold stiffness can be adopted to reproduce the mechanosensory properties assumed by tissues in physiological or pathological conditions. Moreover, the recent development of iPSC-derived 3D brain cultures, called organoids, has made it possible to study key aspects of embryonic brain development, such as neuronal differentiation, maturation and network formation in temporal dynamics that are inaccessible to traditional in vitro cultures. Despite the huge potential of organoids, their application to myelination studies is still in its infancy. In this review, we shall summarize the novel most relevant experimental approaches and their implications for the identification of remyelinating agents for human diseases such as multiple sclerosis.
    Keywords:  co-cultures; hiPSCs; models; myelination; neurodegenerative diseases; oligodendrocytes; organoids
    DOI:  https://doi.org/10.3389/fncel.2021.748849
  25. Brain Res Bull. 2021 Oct 27. pii: S0361-9230(21)00309-9. [Epub ahead of print]
    The neuroprotective effects of Insulin-Like Growth Factor 1 via the Hippo/YAP signaling pathway are mediated by the PI3K/AKT cascade following cerebral ischemia/reperfusion injury.
    Pian Gong, Yichun Zou, Wei Zhang, Qi Tian, Shoumeng Han, Zhou Xu, Qianxue Chen, Xin Wang, Mingchang Li.
      Insulin-like growth factor 1 (IGF-1) has neuroprotective actions, including vasodilatory, anti-inflammatory, and antithrombotic effects, following ischemic stroke. However, the molecular mechanisms underlying the neuroprotective effects of IGF-1 following ischemic stroke remain unknown. Therefore, in the present study, we investigated whether IGF-1 exerted its neuroprotective effects by regulating the Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT cascade, following ischemic stroke. In the in vitro study, we exposed cultured PC12 and SH-5YSY cells, and cortical primary neurons, to oxygen-glucose deprivation. Cell viability was measured using CCK-8 assay. In the in vivo study, Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neurological function was assessed using a modified neurologic scoring system and the modified neurological severity score (mNSS) test, brain edema was detected by brain water content measurement, infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis were evaluated by TUNEL/NeuN double staining, HE and Nissl staining, and immunohistochemistry staining for NeuN. Finally, western blot analysis was used to measure the level of IGF-1 in vivo and levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and reduced neurological deficits, brain water content, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were blocked by an inhibitor of the PI3K/AKT cascade, LY294002. LY294002 treatment not only downregulated PI3K and p-AKT, but YAP/TAZ as well, leading to aggravation of neurological dysfunction and worsening of brain damage. Our findings indicate that the neuroprotective effects of IGF-1 are, at least in part mediated by upregulation of YAP/TAZ via activation of the PI3K/AKT cascade following cerebral ischemic stroke.
    Keywords:  Hippo/YAP signaling pathway; Insulin-like growth factor 1; Ischemia/reperfusion injury; Ischemic stroke; PI3K/AKT signaling pathway
    DOI:  https://doi.org/10.1016/j.brainresbull.2021.10.017
  26. Biol Trace Elem Res. 2021 Nov 02.
    The Role of Zinc Status on Spatial Memory, Hippocampal Synaptic Plasticity, and Insulin Signaling in icv-STZ-Induced Sporadic Alzheimer's-Like Disease in Rats.
    Saltuk Bugra Baltaci, Omer Unal, Elif Gulbahce-Mutlu, Haluk Gumus, Suray Pehlivanoglu, Ahmet Yardimci, Rasim Mogulkoc, Abdulkerim Kasim Baltaci.
      Alzheimer's disease (AD), especially its sporadic form (sAD), is of multifactorial nature. Brain insulin resistance and disrupted zinc homeostasis are two key aspects of AD that remain to be elucidated. Here, we investigated the effects of dietary zinc deficiency and supplementation on memory, hippocampal synaptic plasticity, and insulin signaling in intracerebroventricular streptozotocin (icv-STZ)-induced sAD in rats. The memory performance was evaluated by Morris water maze. The expression of hippocampal protein and mRNA levels of targets related to synaptic plasticity and insulin pathway was assessed by Western blot and real-time quantitative PCR. We found memory deficits in icv-STZ rats, which were fully recovered by zinc supplementation. Western blot analysis revealed that icv-STZ treatment significantly reduced hippocampal PSD95 and p-GSK3β, and zinc supplementation restored the normal protein levels. mRNA levels of BDNF, PSD95, SIRT1, GLUT4, insulin receptor, and ZnT3 were found to be reduced by icv-STZ and reestablished by zinc supplementation. Our data suggest that zinc supplementation improves cognitive deficits and rescues the decline in key molecular targets of synaptic plasticity and insulin signaling in hippocampus caused by icv-STZ induced sAD in rats.
    Keywords:  Alzheimer’s disease; Brain insulin resistance; Learning and memory; Neurodegeneration; Synaptic plasticity; Zinc
    DOI:  https://doi.org/10.1007/s12011-021-02999-2
  27. Front Aging Neurosci. 2021 ;13 755164
    Inhibition of Rho Kinase by Fasudil Ameliorates Cognition Impairment in APP/PS1 Transgenic Mice via Modulation of Gut Microbiota and Metabolites.
    Yuqing Yan, Ye Gao, Qingli Fang, Nianping Zhang, Gajendra Kumar, Hailong Yan, Lijuan Song, Jiehui Li, Yuna Zhang, Jingxian Sun, Jiawei Wang, Linhu Zhao, Keith Skaggs, Han-Ting Zhang, Cun-Gen Ma.
      Background: Fasudil, a Rho kinase inhibitor, exerts therapeutic effects in a mouse model of Alzheimer's disease (AD), a chronic neurodegenerative disease with progressive loss of memory. However, the mechanisms remain unclear. In addition, the gut microbiota and its metabolites have been implicated in AD. Methods: We examined the effect of fasudil on learning and memory using the Morris water-maze (MWM) test in APPswe/PSEN1dE9 transgenic (APP/PS1) mice (8 months old) treated (i.p.) with fasudil (25 mg/kg/day; ADF) or saline (ADNS) and in age- and gender-matched wild-type (WT) mice. Fecal metagenomics and metabolites were performed to identify novel biomarkers of AD and elucidate the mechanisms of fasudil induced beneficial effects in AD mice. Results: The MWM test showed significant improvement of spatial memory in APP/PS1 mice treated with fasudil as compared to ADNS. The metagenomic analysis revealed the abundance of the dominant phyla in all the three groups, including Bacteroidetes (23.7-44%) and Firmicutes (6.4-26.6%), and the increased relative abundance ratio of Firmicutes/Bacteroidetes in ADNS (59.1%) compared to WT (31.7%). In contrast, the Firmicutes/Bacteroidetes ratio was decreased to the WT level in ADF (32.8%). Lefse analysis of metagenomics identified s_Prevotella_sp_CAG873 as an ADF potential biomarker, while s_Helicobacter_typhlonius and s_Helicobacter_sp_MIT_03-1616 as ADNS potential biomarkers. Metabolite analysis revealed the increment of various metabolites, including glutamate, hypoxanthine, thymine, hexanoyl-CoA, and leukotriene, which were relative to ADNS or ADF microbiota potential biomarkers and mainly involved in the metabolism of nucleotide, lipids and sugars, and the inflammatory pathway. Conclusions: Memory deficit in APP/PS1 mice was correlated with the gut microbiome and metabolite status. Fasudil reversed the abnormal gut microbiota and subsequently regulated the related metabolisms to normal in the AD mice. It is believed that fasudil can be a novel strategy for the treatment of AD via remodeling of the gut microbiota and metabolites. The novel results also provide valuable references for the use of gut microbiota and metabolites as diagnostic biomarkers and/or therapeutic targets in clinical studies of AD.
    Keywords:  APP/PS1 double transgenic AD mouse; Alzheimer's disease; Morris water maze; cognition; gut microbiota; metabolite; metagenomics
    DOI:  https://doi.org/10.3389/fnagi.2021.755164
  28. Biol Rev Camb Philos Soc. 2021 Nov 03.
    Microbes, metabolites and (synaptic) malleability, oh my! The effect of the microbiome on synaptic plasticity.
    Ayala Glinert, Sondra Turjeman, Evan Elliott, Omry Koren.
      The microbiome influences the emotional and cognitive phenotype of its host, as well as the neurodevelopment and pathophysiology of various brain processes and disorders, via the well-established microbiome-gut-brain axis. Rapidly accumulating data link the microbiome to severe neuropsychiatric disorders in humans, including schizophrenia, Alzheimer's and Parkinson's. Moreover, preclinical work has shown that perturbation of the microbiome is closely associated with social, cognitive and behavioural deficits. The potential of the microbiome as a diagnostic and therapeutic tool is currently undercut by a lack of clear mechanistic understanding of the microbiome-gut-brain axis. This review establishes the hypothesis that the mechanism by which this influence is carried out is synaptic plasticity - long-term changes to the physical and functional neuronal structures that enable the brain to undertake learning, memory formation, emotional regulation and more. By examining the different constituents of the microbiome-gut-brain axis through the lens of synaptic plasticity, this review explores the diverse aspects by which the microbiome shapes the behaviour and mental wellbeing of the host. Key elements of this complex bi-directional relationship include neurotransmitters, neuronal electrophysiology, immune mediators that engage with both the central and enteric nervous systems and signalling cascades that trigger long-term potentiation of synapses. The importance of establishing mechanistic correlations along the microbiome-gut-brain axis cannot be overstated as they hold the potential for furthering current understanding regarding the vast fields of neuroscience and neuropsychiatry. This review strives to elucidate the promising theory of microbiome-driven synaptic plasticity in the hope of enlightening current researchers and inspiring future ones.
    Keywords:  central nervous system (CNS); enteric nervous system (ENS); immune system; long-term potentiation (LTP); microbiome; neurons; neurotransmitters; synaptic plasticity
    DOI:  https://doi.org/10.1111/brv.12812
  29. Curr Alzheimer Res. 2021 Oct 22.
    Functional Roles of Neuronal Nitric Oxide Synthase in Neurodegenerative Diseases and Mood Disorders.
    Chi Him Poon, Ka Chun Tsui, Sze Chun Chau, Pit Shan Chong, Sylvia Wing Yan Lui, Luca Aquili, Kah Hui Wong, Lee Wei Lim.
      Nitric oxide synthase (NOS) is well known for its involvement in the regulation of the nervous, cardiovascular, and immune systems. Neuronal NOS (nNOS) is the most characterized NOS among all the isoforms. It accounts for most of the production of nitric oxide (NO) in the ner- vous system required for synaptic transmission and neuroplasticity. Previous studies have described the localization of nNOS in specific brain regions of interest. There is substantial evidence in the literature suggesting that nNOS signaling has significant involvement in several disease pathologies. However, the association between brain nNOS expression profiles and disease remains largely unknown. In this review, we attempt to delineate the contribution of nNOS signaling in memory and mood disorders in order to achieve a better understanding of nNOS in disease modulation.
    Keywords:  Alzheimer's disease; Huntington’s disease; Nitric oxide synthase; Parkinson’s disease; mood disorders
    DOI:  https://doi.org/10.2174/1567205018666211022164025
  30. Neuroreport. 2021 Dec 08. 32(17): 1349-1356
    O-GlcNAcase inhibitor has protective effects in intracerebral hemorrhage by suppressing the inflammatory response.
    Yating He, Haijie Liu, Ye Liu, Xiaowen Li, Mengmeng Fan, Kaibin Shi, Minshu Li.
       BACKGROUND: Intracerebral hemorrhage (ICH) is aggravated by immune cells that participate in the inflammatory response from the blood-brain barrier (BBB). O-Glycosylation has been reported to regulate the inflammatory response in the central nervous system but its cerebral protective effects remain unknown. Therefore, this study was carried out to investigate the protective effects of O-GlcNAcylation in a murine model of ICH and the possible mechanisms involved.
    METHODS: The effects of O-GlcNAcylation on hematoma and edema formation were tested using pathological and dry/wet weight methods, whereas its effects on neural function were determined using neurologic tests. The effect of O-GlcNAcylation on BBB integrity was determined by Evans blue dye extrusion. Flow cytometry was used to quantify the immune cells in the central nervous system. Immunofluorescence was used to detect the protective effect of O-GlcNAcylation in ICH.
    RESULTS: The hematoma volume was significantly lower in the prevention and treatment groups than in the control group after ICH induction, indicating that O-GlcNAcylation had reduced the formation of cerebral hematoma in ICH. In the prevention and treatment groups, the modified neurological severity score, corner turn test and rotating rod test results were improved and the BBB integrity was better than that in the control group. O-GlcNAcylation also regulated the microglia, neutrophils and other central nervous system immune cells after ICH, effectively reducing the inflammatory response.
    CONCLUSIONS: O-GlcNAcylation played an important role in suppressing the inflammatory response, enhancing the BBB integrity and reducing edema after ICH.
    DOI:  https://doi.org/10.1097/WNR.0000000000001734
  31. Front Aging Neurosci. 2021 ;13 747989
    SIRT6 Through the Brain Evolution, Development, and Aging.
    Alfredo Garcia-Venzor, Debra Toiber.
      During an organism's lifespan, two main phenomena are critical for the organism's survival. These are (1) a proper embryonic development, which permits the new organism to function with high fitness, grow and reproduce, and (2) the aging process, which will progressively undermine its competence and fitness for survival, leading to its death. Interestingly these processes present various similarities at the molecular level. Notably, as organisms became more complex, regulation of these processes became coordinated by the brain, and failure in brain activity is detrimental in both development and aging. One of the critical processes regulating brain health is the capacity to keep its genomic integrity and epigenetic regulation-deficiency in DNA repair results in neurodevelopmental and neurodegenerative diseases. As the brain becomes more complex, this effect becomes more evident. In this perspective, we will analyze how the brain evolved and became critical for human survival and the role Sirt6 plays in brain health. Sirt6 belongs to the Sirtuin family of histone deacetylases that control several cellular processes; among them, Sirt6 has been associated with the proper embryonic development and is associated with the aging process. In humans, Sirt6 has a pivotal role during brain aging, and its loss of function is correlated with the appearance of neurodegenerative diseases such as Alzheimer's disease. However, Sirt6 roles during brain development and aging, especially the last one, are not observed in all species. It appears that during the brain organ evolution, Sirt6 has gained more relevance as the brain becomes bigger and more complex, observing the most detrimental effect in the brains of Homo sapiens. In this perspective, we part from the evolution of the brain in metazoans, the biological similarities between brain development and aging, and the relevant functions of Sirt6 in these similar phenomena to conclude with the evidence suggesting a more relevant role of Sirt6 gained in the brain evolution.
    Keywords:  DNA damage; Sirtuin 6; Sirtuins; brain aging; brain development; epigenetics; neurodegeneration; neurogenesis
    DOI:  https://doi.org/10.3389/fnagi.2021.747989
  32. Front Aging Neurosci. 2021 ;13 748637
    Cefazolin Improves Anesthesia and Surgery-Induced Cognitive Impairments by Modulating Blood-Brain Barrier Function, Gut Bacteria and Short Chain Fatty Acids.
    Ailin Luo, Shan Li, Xuan Wang, Zheng Xie, Shiyong Li, Dongyu Hua.
      Emerging evidence suggests that anesthesia and surgery may induce gut dysbiosis. Gut dysbiosis leads to imbalance in circulating contents of microbiota-derived metabolites and disrupts the integrity of the blood-brain barrier (BBB), contributing to postoperative cognitive dysfunction (POCD). The composition of gut microbiota may be influenced by various antibiotics. However, how perioperative use of antibiotics affects POCD needs more explorations. In the present study, we explored the effect of cefazolin, a common antibiotic used in perioperative period, on cognitive function, BBB integrity, gut bacteria and short chain fatty acids (SCFAs), a group of widely studied metabolites in aged mice, using 18-month-old male mice. Significant BBB disruptions and decreased levels of tight junction proteins, zonula occludens-1 (ZO-1) and Occludin (OCLN) were seen in the mice of POCD model. Cefazolin treatment attenuated these changes induced by anesthesia and surgery. Furthermore, cefazolin reversed the changes in several fecal bacteria (β-, γ/δ-, ε-Proteobacteria, and Bacteroidetes) as determined by qPCR tests. Analysis of plasma SCFAs showed that almost all types of SCFAs were reduced in POCD and cefazolin administration reversed the changes in expression of the two most abundant SCFAs (acetic and propionic acids). In conclusion, this study demonstrated that cefazolin improved POCD. Mechanistically, cefazolin suppressed the disruption of BBB, gut microbiota or SCFAs, thereby ameliorating POCD.
    Keywords:  blood-brain barrier; cefazolin; gut microbiota; postoperative cognitive dysfunction (POCD); short chain fatty acids
    DOI:  https://doi.org/10.3389/fnagi.2021.748637
  33. BMC Biol. 2021 Nov 03. 19(1): 236
    Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster.
    Guiran Xiao, Mengran Zhao, Zhihua Liu, Fan Du, Bing Zhou.
       BACKGROUND: Dopamine (DA) is a neurotransmitter that plays roles in movement, cognition, attention, and reward responses, and deficient DA signaling is associated with the progression of a number of neurological diseases, such as Parkinson's disease. Due to its critical functions, DA expression levels in the brain are tightly controlled, with one important and rate-limiting step in its biosynthetic pathway being catalyzed by tyrosine hydroxylase (TH), an enzyme that uses iron ion (Fe2+) as a cofactor. A role for metal ions has additionally been associated with the etiology of Parkinson's disease. However, the way dopamine synthesis is regulated in vivo or whether regulation of metal ion levels is a component of DA synthesis is not fully understood. Here, we analyze the role of Catsup, the Drosophila ortholog of the mammalian zinc transporter SLC39A7 (ZIP7), in regulating dopamine levels.
    RESULTS: We found that Catsup is a functional zinc transporter that regulates intracellular zinc distribution between the ER/Golgi and the cytosol. Loss-of-function of Catsup leads to increased DA levels, and we showed that the increased dopamine production is due to a reduction in zinc levels in the cytosol. Zinc ion (Zn2+) negatively regulates dopamine synthesis through direct inhibition of TH activity, by antagonizing Fe2+ binding to TH, thus rendering the enzyme ineffective or non-functional.
    CONCLUSIONS: Our findings uncovered a previously unknown mechanism underlying the control of cellular dopamine expression, with normal levels of dopamine synthesis being maintained through a balance between Fe2+ and Zn2+ ions. The findings also provide support for metal modulation as a possible therapeutic strategy in the treatment of Parkinson's disease and other dopamine-related diseases.
    Keywords:  Catecholamines up; Iron; Parkinson’s disease; Tyrosine hydroxylase; Zinc
    DOI:  https://doi.org/10.1186/s12915-021-01168-0
  34. Insect Biochem Mol Biol. 2021 Nov 01. pii: S0965-1748(21)00157-0. [Epub ahead of print] 103674
    Deformed wing virus infection affects the neurological function of Apis mellifera by altering extracellular adenosine signaling.
    Ping Chen, Yun-Heng Lu, Yu-Hsien Lin, Carol-P Wu, Cheng-Kang Tang, Sung-Chan Wei, Yueh-Lung Wu.
      Deformed wing virus (DWV) infection is believed to be closely associated with colony losses of honeybee (Apis mellifera) due to reduced learning and memory of infected bees. The adenosine (Ado) pathway is important for maintaining immunity and memory function in animals, and it enhances antivirus responses by regulating carbohydrate metabolism in insects. Nevertheless, its effect on the memory of invertebrates is not yet clear. This study investigated how the Ado pathway regulates energy metabolism and memory in honeybees following DWV infection. Decreased Ado receptor (Ado-R) expression in the brain of infected bees resulted in a carbohydrate imbalance as well as impairments of glutamate-glutamine (Glu-Gln) cycle and long-term memory. Dietary supplementation with Ado not only increased the brain energy metabolism but also rescued long-term memory loss by upregulating the expression of memory-related genes. The present study demonstrated the regulation of the Ado pathway upon DWV infection and provides insights into the mechanisms underlying energy regulation and the neurological function of honeybees.
    Keywords:  Adenosine; Deformed wing virus (DWV); Honeybee (Apis mellifera); Long-term memory
    DOI:  https://doi.org/10.1016/j.ibmb.2021.103674
  35. J Neurosci. 2021 Oct 27. pii: JN-RM-1502-21. [Epub ahead of print]
    A Pro-inflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol.
    Yukitoshi Izumi, Anil Cashikar, Kathiresan Krishnan, Steven M Paul, Douglas F Covey, Steven J Mennerick, Charles F Zorumski.
      Inflammatory cells including macrophages and microglia synthesize and release the oxysterol, 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild type microglia produced higher levels of 25HC than Ch25h knockout (KO) microglial with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo, LPS treatment also disrupts LTP and inhibits one-trial learning in wild type but not Ch25h KO mice. These results demonstrate that the oxysterol, 25HC, is a key modulator of synaptic plasticity and memory under proinflammatory stimuli.SIGNIFICANCE STATEMENTNeuroinflammation is thought to contribute to cognitive impairment in multiple neuropsychiatric illnesses. In this study, we found that a pro-inflammatory stimulus, LPS, disrupts hippocampal LTP via a metaplastic mechanism. The effects of LPS on LTP are mimicked by the oxysterol, 25HC, an immune mediator synthesized in brain microglia. Effects of LPS on both synaptic plasticity and one-trial inhibitory avoidance learning are eliminated in mice deficient in Ch25h, the primary enzyme responsible for endogenous 25HC synthesis. Thus, these results indicate that 25HC is a key mediator of the effects of an inflammatory stimulus on hippocampal function and open new potential avenues to overcome the effects of neuroinflammation on brain function.
    DOI:  https://doi.org/10.1523/JNEUROSCI.1502-21.2021
  36. Med Res Rev. 2021 Nov 03.
    Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases.
    Li Wang, Jiajia Li, Li-Jun Di.
      Glycogen synthase kinase-3 (GSK3) is a highly evolutionarily conserved serine/threonine protein kinase first identified as an enzyme that regulates glycogen synthase (GS) in response to insulin stimulation, which involves GSK3 regulation of glucose metabolism and energy homeostasis. Both isoforms of GSK3, GSK3α, and GSK3β, have been implicated in many biological and pathophysiological processes. The various functions of GSK3 are indicated by its widespread distribution in multiple cell types and tissues. The studies of GSK3 activity using animal models and the observed effects of GSK3-specific inhibitors provide more insights into the roles of GSK3 in regulating energy metabolism and homeostasis. The cross-talk between GSK3 and some important energy regulators and sensors and the regulation of GSK3 in mitochondrial activity and component function further highlight the molecular mechanisms in which GSK3 is involved to regulate the metabolic activity, beyond its classical regulatory effect on GS. In this review, we summarize the specific roles of GSK3 in energy metabolism regulation in tissues that are tightly associated with energy metabolism and the functions of GSK3 in the development of metabolic disorders. We also address the impacts of GSK3 on the regulation of mitochondrial function, activity and associated metabolic regulation. The application of GSK3 inhibitors in clinical tests will be highlighted too. Interactions between GSK3 and important energy regulators and GSK3-mediated responses to different stresses that are related to metabolism are described to provide a brief overview of previously less-appreciated biological functions of GSK3 in energy metabolism and associated diseases through its regulation of GS and other functions.
    Keywords:  GSK3; energy homeostasis; glucose metabolism; insulin sensitivity; metabolic regulators; stress response
    DOI:  https://doi.org/10.1002/med.21867
  37. Am J Physiol Gastrointest Liver Physiol. 2021 Nov 03.
    Gut Feelings: The Microbiota-Gut-Brain Axis on Steroids.
    Sik Yu So, Tor C Savidge.
      The intricate connection between central and enteric nervous systems is well established with emerging evidence linking gut microbiota function as a significant new contributor to gut-brain axis signaling. Several microbial signals contribute to altered gut-brain communications, with steroids representing an important biological class that impacts central and enteric nervous system function. Neuroactive steroids contribute pathologically to neurological disorders, including dementia and depression, by modulating the activity of neuroreceptors. However, limited information is available on the influence of neuroactive steroids on the enteric nervous system and gastrointestinal function. In this review, we outline how steroids can modulate enteric nervous system function by focusing on their influence on different receptors that are present in the intestine in health and disease. We also highlight the potential role of the gut microbiota in modulating neuroactive steroid signaling along the gut-brain axis.
    Keywords:  Steroids; enteric nervous system; gut-brain axis; microbiome; neurosteroids
    DOI:  https://doi.org/10.1152/ajpgi.00294.2021
  38. Alzheimers Res Ther. 2021 Nov 02. 13(1): 181
    The apolipoprotein receptor LRP3 compromises APP levels.
    Inmaculada Cuchillo-Ibañez, Matthew P Lennol, Sergio Escamilla, Trinidad Mata-Balaguer, Lucía Valverde-Vozmediano, Inmaculada Lopez-Font, Isidro Ferrer, Javier Sáez-Valero.
       BACKGROUND: Members of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in amyloid precursor protein (APP) processing and β-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. We have analyzed whether ApoER2-ICD is able to regulate the expression of other LDL receptors, and we focused on LRP3, the most unknown member of this family. We analyzed LRP3 expression in middle-aged individuals (MA) and in cases with Alzheimer's disease (AD)-related pathology, and the relation of LRP3 with APP.
    METHODS: The effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in the presence of recombinant reelin or Aβ42 peptide, were evaluated by microarray, qRT-PCRs, and western blots in SH-SY5Y cells. LRP3 expression was analyzed in human frontal cortex extracts from MA subjects (mean age 51.8±4.8 years) and AD-related pathology subjects [Braak neurofibrillary tangle stages I-II, 68.4±8.8 years; III-IV, 80.4 ± 8.8 years; V-VI, 76.5±9.7 years] by qRT-PCRs and western blot; LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Chloroquine was employed to block the lysosomal/autophagy function.
    RESULTS: We have identified that ApoER2 overexpression increases LRP3 expression, also after reelin stimulation of ApoER2 signaling. The same occurred following ApoER2-ICD overexpression. In extracts from subjects with AD-related pathology, the levels of LRP3 mRNA and protein were lower than those in MA subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, particularly in the membrane fraction. In cell supernatants, levels of APP fragments from the amyloidogenic (sAPPα) or non-amyloidogenic (sAPPβ) pathways, as well as Aβ peptides, were drastically reduced with respect to mock-transfected cells. The inhibitor of lysosomal/autophagy function, chloroquine, significantly increased full-length APP, APP-CTF, and sAPPα levels.
    CONCLUSIONS: ApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.
    Keywords:  Alzheimer’s disease; ApoER2; ApoER2-ICD; Autophagy; Beta-amyloid; Chloroquine; Differential centrifugation; sAPP
    DOI:  https://doi.org/10.1186/s13195-021-00921-5
  39. Front Physiol. 2021 ;12 712317
    Hypoxia-Induced Neuroinflammation in Alzheimer's Disease: Potential Neuroprotective Effects of Centella asiatica.
    Aqilah Hambali, Jaya Kumar, Nur Fariesha Md Hashim, Sandra Maniam, Muhammad Zulfadli Mehat, Manraj Singh Cheema, Muzaimi Mustapha, Mohd Ilham Adenan, Johnson Stanslas, Hafizah Abdul Hamid.
      Alzheimer's disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.
    Keywords:  Alzheimer’s disease; Centella asiatica; NF-κβ; Nrf2; hypoxia; neurodegenerative disease; neuroinflammation; neuroprotective
    DOI:  https://doi.org/10.3389/fphys.2021.712317
  40. J Alzheimers Dis. 2021 Oct 25.
    Calpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer's Disease.
    Bruna Schultz, Jéssica Taday, Leonardo Menezes, Anderson Cigerce, Marina C Leite, Carlos-Alberto Gonçalves.
      One of the changes found in the brain in Alzheimer's disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and 2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-β clearance in astrocytes, as opposed to amyloid-β accumulation in neurons.
    Keywords:  Alzheimer’s disease; CDK5; GFAP; S100B; astrocyte; calcineurin; calpain
    DOI:  https://doi.org/10.3233/JAD-215182
  41. Cell Biosci. 2021 Nov 02. 11(1): 188
    Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.
    Shuqi Du, Hui Zheng.
      Aging happens to all of us as we live. Thanks to the improved living standard and discovery of life-saving medicines, our life expectancy has increased substantially across the world in the past century. However, the rise in lifespan leads to unprecedented increases in both the number and the percentage of individuals 65 years and older, accompanied by the increased incidences of age-related diseases such as type 2 diabetes mellitus and Alzheimer's disease. FoxO transcription factors are evolutionarily conserved molecules that play critical roles in diverse biological processes, in particular aging and metabolism. Their dysfunction is often found in the pathogenesis of many age-related diseases. Here, we summarize the signaling pathways and cellular functions of FoxO proteins. We also review the complex role of FoxO in aging and age-related diseases, with focus on type 2 diabetes and Alzheimer's disease and discuss the possibility of FoxO as a molecular link between aging and disease risks.
    Keywords:  Age-related disease; Aging; Alzheimer’s disease; FoxO; Type 2 diabetes mellitus
    DOI:  https://doi.org/10.1186/s13578-021-00700-7
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