scholarly journals Metabolic Plasticity of Astrocytes and Aging of the Brain

2019 ◽  
Vol 20 (4) ◽  
pp. 941 ◽  
Author(s):  
Mitsuhiro Morita ◽  
Hiroko Ikeshima-Kataoka ◽  
Marko Kreft ◽  
Nina Vardjan ◽  
Robert Zorec ◽  
...  
Keyword(s):  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Acid Oxidation ◽  
Normal Brain ◽  
Atp Production ◽  
Metabolic Plasticity ◽  
Neuronal Synapses ◽  
Age Related ◽  
Pathologic Processes ◽  
The Brain

As part of the blood-brain-barrier, astrocytes are ideally positioned between cerebral vasculature and neuronal synapses to mediate nutrient uptake from the systemic circulation. In addition, astrocytes have a robust enzymatic capacity of glycolysis, glycogenesis and lipid metabolism, managing nutrient support in the brain parenchyma for neuronal consumption. Here, we review the plasticity of astrocyte energy metabolism under physiologic and pathologic conditions, highlighting age-dependent brain dysfunctions. In astrocytes, glycolysis and glycogenesis are regulated by noradrenaline and insulin, respectively, while mitochondrial ATP production and fatty acid oxidation are influenced by the thyroid hormone. These regulations are essential for maintaining normal brain activities, and impairments of these processes may lead to neurodegeneration and cognitive decline. Metabolic plasticity is also associated with (re)activation of astrocytes, a process associated with pathologic events. It is likely that the recently described neurodegenerative and neuroprotective subpopulations of reactive astrocytes metabolize distinct energy substrates, and that this preference is supposed to explain some of their impacts on pathologic processes. Importantly, physiologic and pathologic properties of astrocytic metabolic plasticity bear translational potential in defining new potential diagnostic biomarkers and novel therapeutic targets to mitigate neurodegeneration and age-related brain dysfunctions.

ABC Transporters in Neurological Disorders: An Important Gateway for Botanical Compounds Mediated Neuro-Therapeutics

2019 ◽  
Vol 19 (10) ◽  
pp. 795-811 ◽  
Author(s):  
Niraj Kumar Jha ◽  
Rohan Kar ◽  
Rituraj Niranjan
Keyword(s):  
Abc Transporters ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Brain Parenchyma ◽  
Normal Brain ◽  
Neurological Outcomes ◽  
Age Related ◽  
Number Of Factors ◽  
Vector Borne ◽  
The Brain

Neurodegeneration is a distinguishing feature of many age related disorders and other vector borne neuroinflammatory diseases. There are a number of factors that can modulate the pathology of these disorders. ATP-binding cassette (ABC) transporters are primarily involved in the maintenance of normal brain homeostasis by eliminating toxic peptides and compounds from the brain. Also, ABC transporters protect the brain from the unwanted effects of endogenous and exogenous toxins that can enter the brain parenchyma. Therefore, these transporters have the ability to determine the pathological outcomes of several neurological disorders. For instance, ABC transporters like P-glycoprotein (ABCB1), and BCRP (ABCG2) have been reported to facilitate the clearance of peptides such as amyloid-β (Aβ) that accumulate in the brain during Alzheimer’s disease (AD) progression. Other members such as ABCA1, ABCA2, ABCC8, ABCC9, ABCG1 and ABCG4 also have been reported to be involved in the progression of various brain disorders such as HIV-associated dementia, Multiple sclerosis (MS), Ischemic stroke, Japanese encephalitis (JE) and Epilepsy. However, these defective transporters can be targeted by numerous botanical compounds such as Verapamil, Berberine and Fascalpsyn as a therapeutic target to treat these neurological outcomes. These compounds are already reported to modulate ABC transporter activity in the CNS. Nonetheless, the exact mechanisms involving the ABC transporters role in normal brain functioning, their role in neuronal dysfunction and how these botanical compounds ensure and facilitate their therapeutic action in association with defective transporters still remain elusive. This review therefore, summarizes the role of ABC transporters in neurological disorders, with a special emphasis on its role in AD brains. The prospect of using botanical/natural compounds as modulators of ABC transporters in neurological disorders is discussed in the latter half of the article.

scholarly journals The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1833
Author(s):  
Shannon Morgan McCabe ◽  
Ningning Zhao
Keyword(s):  
Cerebrospinal Fluid ◽  
Blood Brain Barrier ◽  
Blood Circulation ◽  
Critical Role ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

scholarly journals Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

2020 ◽  
Author(s):  
Andrés Fernández ◽  
Elena Quintana ◽  
Patricia Velasco ◽  
Belén de Andrés ◽  
Maria Luisa Gaspar ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Inflammatory Cytokines ◽  
Hippocampal Formation ◽  
Morphological Changes ◽  
Interleukin 1 ◽  
Brain Parenchyma ◽  
Age Related ◽  
Inflammatory Changes ◽  
Samp8 Mice ◽  
The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

scholarly journals The glymphatic system and its role in cerebral homeostasis

2020 ◽  
Vol 129 (6) ◽  
pp. 1330-1340
Author(s):  
Helene Benveniste ◽  
Rena Elkin ◽  
Paul M. Heerdt ◽  
Sunil Koundal ◽  
Yuechuan Xue ◽  
...  
Keyword(s):  
Brain Parenchyma ◽  
Toxic Waste ◽  
Normal Brain ◽  
Fluid Exchange ◽  
Glymphatic System ◽  
The Past ◽  
System A ◽  
Waste Production ◽  
Lymphatic Vasculature ◽  
The Brain

The brain’s high bioenergetic state is paralleled by high metabolic waste production. Authentic lymphatic vasculature is lacking in brain parenchyma. Cerebrospinal fluid (CSF) flow has long been thought to facilitate central nervous system detoxification in place of lymphatics, but the exact processes involved in toxic waste clearance from the brain remain incompletely understood. Over the past 8 yr, novel data in animals and humans have begun to shed new light on these processes in the form of the “glymphatic system,” a brain-wide perivascular transit passageway dedicated to CSF transport and interstitial fluid exchange that facilitates metabolic waste drainage from the brain. Here we will discuss glymphatic system anatomy and methods to visualize and quantify glymphatic system (GS) transport in the brain and also discuss physiological drivers of its function in normal brain and in neurodegeneration.

scholarly journals Hypoxic-Ischaemic Encephalopathy and the Blood-Brain Barrier in Neonates

2017 ◽  
Vol 39 (1-4) ◽  
pp. 49-58 ◽  
Author(s):  
Wei Ling Amelia Lee ◽  
Adina T. Michael-Titus ◽  
Divyen K. Shah
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Circulation ◽  
Brain Parenchyma ◽  
Cerebral Injury ◽  
Brain Barrier ◽  
Transport Systems ◽  
Permeability Barrier ◽  
Cell Based Therapy ◽  
Blood Brain ◽  
The Brain

This review aims to highlight a possible relationship between hypoxic-ischaemic encephalopathy (HIE) and the disruption of the blood-brain barrier (BBB). Inflammatory reactions perpetuate a large proportion of cerebral injury. The extent of injury noted in HIE is not only determined by the biochemical cascades that trigger the apoptosis-necrosis continuum of cell death in the brain parenchyma, but also by the breaching of the BBB by pro-inflammatory factors. We examine the changes that contribute to the breakdown of the BBB that occur during HIE at a macroscopic, cellular, and molecular level. The BBB is a permeability barrier which separates a large majority of brain areas from the systemic circulation. The concept of a physiological BBB is based at the anatomical level on the neurovascular unit (NVU). The NVU consists of various cellular components that jointly regulate the exchanges that occur at the interface between the systemic circulation and the brain parenchyma. There is increased understanding of the contribution of the components of the NVU, e.g., astrocytes and pericytes, to the maintenance of this physiological barrier. We also explore the development of therapeutic options in HIE, such as harnessing the transport systems in the BBB, to enable the delivery of large molecules with molecular Trojan horse technology, and the reinforcement of the physical barrier with cell-based therapy which utilizes endothelial progenitor cells and stem cells.

Age-related changes in microglial physiology: the role for healthy brain ageing and neurodegenerative disorders

e-Neuroforum ◽  
2017 ◽  
Vol 23 (4) ◽  
Author(s):  
Olga Garaschuk
Keyword(s):  
Neurodegenerative Disorders ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Brain Parenchyma ◽  
Immune Defense ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Age Related ◽  
Brain Ageing ◽  
The Brain

AbstractMicroglia are the main immune cells of the brain contributing, however, not only to brain’s immune defense but also to many basic housekeeping functions such as development and maintenance of functional neural networks, provision of trophic support for surrounding neurons, monitoring and modulating the levels of synaptic activity, cleaning of accumulating extracellular debris and repairing microdamages of the brain parenchyma. As a consequence, age-related alterations in microglial function likely have a manifold impact on brain’s physiology. In this review, I discuss the recent data about physiological properties of microglia in the adult mammalian brain; changes observed in the brain innate immune system during healthy aging and the probable biological mechanisms responsible for them as well as changes occurring in humans and mice during age-related neurodegenerative disorders along with underlying cellular/molecular mechanisms. Together these data provide a new conceptual framework for thinking about the role of microglia in the context of age-mediated brain dysfunction.

scholarly journals Physiology of Microglia

2011 ◽  
Vol 91 (2) ◽  
pp. 461-553 ◽  
Author(s):  
Helmut Kettenmann ◽  
Uwe-Karsten Hanisch ◽  
Mami Noda ◽  
Alexei Verkhratsky
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Brain Parenchyma ◽  
Microglial Cells ◽  
Activation Process ◽  
Normal Brain ◽  
The Central Nervous System ◽  
Cellular Compartments ◽  
The Brain

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed “resting microglia.” Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the “activated microglial cell.” This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

scholarly journals Probabilistic Critical Controllability Analysis of Protein Interaction Networks Integrating Normal Brain Ageing Gene Expression Profiles

2021 ◽  
Vol 22 (18) ◽  
pp. 9891
Author(s):  
Eimi Yamaguchi ◽  
Tatsuya Akutsu ◽  
Jose C. Nacher
Keyword(s):  
Gene Expression ◽  
Biological Networks ◽  
Expression Profiles ◽  
Dominating Set ◽  
Gene Expression Profiles ◽  
Brain Regions ◽  
Normal Brain ◽  
Age Related ◽  
Brain Ageing ◽  
The Brain

Recently, network controllability studies have proposed several frameworks for the control of large complex biological networks using a small number of life molecules. However, age-related changes in the brain have not been investigated from a controllability perspective. In this study, we compiled the gene expression profiles of four normal brain regions from individuals aged 20–99 years and generated dynamic probabilistic protein networks across their lifespan. We developed a new algorithm that efficiently identified critical proteins in probabilistic complex networks, in the context of a minimum dominating set controllability model. The results showed that the identified critical proteins were significantly enriched with well-known ageing genes collected from the GenAge database. In particular, the enrichment observed in replicative and premature senescence biological processes with critical proteins for male samples in the hippocampal region led to the identification of possible new ageing gene candidates.

Longitudinal diffusion-weighted imaging in infants with hydrocephalus: decrease in tissue water diffusion after cerebrospinal fluid diversion

2009 ◽  
Vol 4 (1) ◽  
pp. 56-63 ◽  
Author(s):  
Paul H. Leliefeld ◽  
Rob H. J. M. Gooskens ◽  
Kees P. J. Braun ◽  
Lino M. P. Ramos ◽  
Cuno S. P. M. Uiterwaal ◽  
...  
Keyword(s):  
Brain Parenchyma ◽  
Periventricular White Matter ◽  
Normal Range ◽  
Arterial Blood ◽  
Diffusion Weighted ◽  
Age Related ◽  
Adc Values ◽  
Csf Diversion ◽  
The Mean ◽  
The Brain

Object Progressive hydrocephalus may lead to edema of the periventricular white matter and to damage of the brain parenchyma because of compression, stretching, and ischemia. The aim of the present study was to investigate whether cerebral edema can be quantified using diffusion-weighted imaging in infants with hydrocephalus and whether CSF diversion could decrease cerebral edema. Methods Diffusion-weighted MR imaging was performed in 24 infants with progressive hydrocephalus before and after CSF diversion. Parametric images of the trace apparent diffusion coefficients (ADCs) were obtained. The ADCs of 5 different cortical and subcortical regions of interest were calculated pre- and postoperatively in each patient. The ADC values were compared with age-related normal values. Mean arterial blood pressure and anterior fontanel pressure were measured immediately after each MR imaging study. Results After CSF diversion, the mean ADC decreased from a preoperative value of 1209 ± 116 × 10−6 mm2/second to a postoperative value of 928 ± 64 × 10−6 mm2/second (p < 0.005). Differences between pre- and postoperative ADC values were most prominent in the periventricular white matter, supporting the existence of preoperative periventricular edema. Compared with age-related normal values, the preoperative ADC values were higher and the postoperative ADC values were lower, although within normal range. The decrease in ADC after CSF drainage was more rapid than the more gradual physiological decrease that is related to age. The preoperative ICP was elevated in all patients. After CSF diversion the ICP decreased significantly to within the normal range. A linear correlation between ADC values and ICP was found (correlation coefficient 0.496, p < 0.001). In all patients the mean arterial blood pressure was within physiological limits both pre- and postoperatively. Conclusions This study shows a rapid and more extensive decrease in ADC values after CSF diversion than is to be expected from physiological ADC decrease solely due to increasing patient age. The preoperative ADC increase can be explained by interstitial edema caused by transependymal CSF leakage or by vasogenic edema caused by capillary compression and stretching of the brain parenchyma. This study population of infants with (early recognized) hydrocephalus did not suffer from cytotoxic edema. These findings may help to detect patients at risk for cerebral damage by differentiating between progressive and compensated hydrocephalus.

scholarly journals Metabolic Maturation of the Brain: A Study of Local Cerebral Glucose Utilization in the Developing Cat

1991 ◽  
Vol 11 (1) ◽  
pp. 35-47 ◽  
Author(s):  
Harry T. Chugani ◽  
David A. Hovda ◽  
Jaime R. Villablanca ◽  
Michael E. Phelps ◽  
Wei-Fang Xu
Keyword(s):  
Developmental Plasticity ◽  
Glucose Utilization ◽  
Biological Significance ◽  
Brain Regions ◽  
Metabolic Plasticity ◽  
Age Related ◽  
Positron Emission ◽  
Baseline Values ◽  
Adult Cats ◽  
The Brain

Previously, using positron emission tomography (PET), we showed that local cerebral metabolic rates for glucose (lCMRglc) in children undergo dynamic maturational trends before reaching adult values. In order to develop an animal model that can be used to explore the biological significance of the different segments of the lCMRglc maturational curve, we measured lCMRglc in kittens at various stages of postnatal development and in adult cats using quantitative [14C]2-deoxyglucose autoradiography. In the kitten, very low lCMRglc levels (0.14 to 0.53 μmol min−1 g−1) were seen during the first 15 days of life, with phylogenetically older brain regions being generally more metabolically mature than newer structures. After 15 days of age, many brain regions (particularly telencephalic structures) underwent sharp increases of lCMRglc to reach, or exceed, adult rates by 60 days. This developmental period (15 to 60 days) corresponds to the time of rapid synaptic proliferation known to occur in the cat. At 90 and 120 days, a slight decline in lCMRglc was observed, but this was followed by a second, larger peak occurring at about 180 days, when sexual maturation occurs in the cat. Only after 180 days did lCMRglc decrease to reach final adult values (0.21 to 2.04 μmol min−1 g−1). In general, there was good correlation between the metabolic maturation of various neuroanatomical regions and the emergence of behaviors mediated by the specific region. At least in the kitten visual cortex, which has been extensively studied with respect to developmental plasticity, the “critical period” corresponded to that portion of the lCMRglc maturational curve surrounding the 60-day metabolic peak. These normal maturational lCMRglc data will serve as baseline values with which to compare anatomical and metabolic plasticity changes induced by age-related lesions in the cat.

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