Figure 1.2: Illustration of a standard motor neuron adapted from Barker... - Scientific Figure on ResearchGate
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Figure 1.2: Illustration of a standard motor neuron adapted from Barker [5]. Processes marked with I were named protoplasmic processes by Otto Deiters [4] and later called dendrites. II points to the cell body. III represents the axon, which was named the axis cylinder by Deiters. IV shows the connection to the muscle (muscular end plate).
ContextIn this chapter the relationship between neurodegeneration and the phospholipid transfer protein phosphatidylinositol transfer protein α (PI-TP α ) is described. As the cellular organisation and function of the brain is a complex subject and a research field on its own, the first part of this chapter comprises an introduction to the different cell types that are present in the brain and the delicate balance between these different cells required for optimal brain function. In addition, several neurodegenerative diseases are discussed in which this balance is clearly disturbed. Finally, using the information presented in the first three paragraphs, the relationship between PI-TP α and neurodegeneration is explained.
functions, such as speech and language, are usually controlled by a particular part of the cerebrum. Contemporary with the interest in brain function, the (cellular) organisation of the central nervous system (brain and spinal cord) has gained attention and has been investigated in more detail. In 1839, Theodor Schwann and Matthias Schleiden developed the cell theory [1] stating the concept that all organisms are composed of similar units of organisation, which they called cells (derived from the Latin word ‘cellula’, meaning ‘small compartment’). At the same time the composition of the central nervous system (CNS) gained attention from histologists, cytologists, and pathologists. During the nineteenth century there was an on-going discussion about the organisation of the CNS. One group of researchers, the ‘reticularists’, argued that the CNS consisted of a network tissue (or reticulum) formed by fused nerve fibers. The other group, called the ‘neuronists’, believed that the CNS consisted of distinct elements or cells. Both groups used the same methods and material to prove their theory, but came to different conclusions because of the poor magnification and resolution of the microscopes that were available at the time. In the early days of brain research, the thoughts of Joseph von Gerlach were believed to hold for the composition of the CNS. Von Gerlach was a true reticularist. He believed that the small processes of nerve cells fused to form a network. Furthermore he assumed that the processes in the network rearrange to form nerve fibers which finally end up in nerves [2]. The first scientist to describe a nerve cell was Johannes Evangelista Purkyne [3]. He used an achromatic compound microscope and a microtome to obtain thin slices of brain tissue. He and others discovered ‘corpuscles’ in the cortex of the cerebral cortex that were situated in rows, containing a nucleus and ‘tail-like endings’ that disappear in the gray matter. This is a description of cells that were later named Purkinje cells, after their discoverer. Using further improvements in microscopy, Otto Deiters [4] was the first to show that the neuronal cell body and its processes, which he named protoplasmic processes (later called dendrites) and the axis cylinder (axon), are continuous
(Figure 1.2, [5]). He believed that dendrites, but not the axons, of different neurons fuse to a continuous network. Apart from the development of the microscope, another significant improvement was made by the discovery of methods that selectively stain distinct parts of nervous tissue. While experimenting with photographic techniques, in 1873 Camillo Golgi treated fixed tissue with silver nitrate for varying lengths of time. A dense precipitate formed on 1-5% of neurons and glia (see next paragraph). The black reaction, as this treatment was called, visualised entire cells [6]. Despite the discovery of a technique that allowed that the CNS could be studied in far more detail, Golgi still believed that the nervous system consisted of a continuous network. The first scientist who doubted the network theory was the Norwegian zoologist Fridtiof Nansen. In 1886 he stated that he found no evidence of a network between nerve cells [7]. In the same year, independently from Nansen, the Swiss embryologist Wilhelm His discovered that during the early development in human embryos nerve cells were not in contact. In addition, The Swiss psychiatrist August Forel in 1887 observed that degeneration in the CNS did not spread, but was restricted to the edge of the cell. Therefore he also disagreed with the network theory (reviewed in [8]). However, it was the Spanish histologist Santiago Ramón y Cajal who stated that all nerve cells were independent units in the CNS. He came to this conclusion by examining nervous tissue from different vertebrates. He improved the black reaction method of Golgi, allowing him to study tissue in more detail. In 1888, Cajal observed that the ‘axis cylinder’ of one cell ended close to ‘protoplasmic processes’ of another cell. This led Cajal to formulate the law of ‘dynamic polarisation’, according to how information runs in one direction through a nerve cell: from the protoplasmic processes through the cell body to the axis cylinder. As Cajal published in Spanish, his ideas did not get many followers until he attended a meeting in Germany in 1889. From that time on ‘the neuron doctrine’, as it was called later, gained more followers and in the end became fully accepted (Together with Camillo Golgi Cajal received the Nobel Prize in 1906). The doctrine stated that: o The fundamental structural and functional unit of the nervous system is the neuron o Neurons are discrete cells which are not continuous with other cells o The neuron is composed of three parts: the dendrites, axon, and cell body, and o Information flows along the neuron in one direction The terminology used above was only introduced in the last decade of the nineteenth century. The term neuron was introduced in 1891 by Vilhelm Von Waldeyer and was derived from the Greek word for tendon (reviewed in [8]). The axis cylinder was named axon by Rudolph von Kollicker and the protoplasmic processes were called dendrites by Wilhelm His. Sir Charles Sherrington described the ‘gap’ between the nerve and muscle and called it synapse in 1897 (composed from the Greek words ‘syn’ meaning together, and ‘haptein’, meaning to hold). In the early 20 th century the pharmacologists Harry Dale and Otto Loewi independently concluded from observations that neurons delivered information by secreting chemical substances that are now generally known as neurotransmitters. The pathologist Rudolph Virchow was the first to describe the space between neurons in the CNS. He stated that this space was filled with connective tissue, derived from the brain, covered by a layer of epithelium. He called this cement-like substance neuroglia (derived from the Greek word glia, meaning glue) and proclaimed that it appeared in the brain and spinal cord and embedded the neurons in these areas [9]. Cell staining techniques were only developed in the 1870s, therefore most of the studies were performed using unstained tissue that was carefully prepared, using fine needles to dissect the tissue apart in order to obtain single cells for investigation. For that reason, the retina was often chosen as study material, as this tissue is relatively thin and as a result less complicated to prepare. In 1856, Heinrich Müller studied the retina and described radial fibers (later called Müller cells), which were, as he stated, non-neuronal cells [10]. Even though Müller’s illustrations of non-neuronal cells in the CNS were convincing (Figure 1.3A, [11]), from a historical point of view Virchow is widely accepted as the scientist who first described non-neuronal cells in the CNS. As described in [12] he states that neuroglia contains cellular elements. The illustration in this paper is considered to be the first image of a non-neuronal cell (Figure 1.3B, [11]). In 1865, Otto Deiters was the first to publish illustrations of glial cells that bear a resemblance to what we now call astrocytes (Figure 1.3C, [11]) [4]. A few years later, Camillo Golgi noted that processes of glial cells contact blood vessels, which is characteristic for astrocytes. He also described glial cells which are located in groups or rows and whose processes were attached to nerve fibers (Figure 1.4, [11]). These are clearly features of cells later named oligodendrocytes [13]. However, from these data he failed to conclude that neuroglia consists of different developed a silver-carbonate staining [17], with which he selectively stained two different cell types. The first type, which was most common in white matter (parts of the brain containing mainly axons), he named oligodendrocytes [18]. This because these cells showed fewer processes compared to astrocytes. As oligodendrocytes showed resemblance in relationship to Schwann cells and myelin, he proposed that oligodendrocytes were the myelin-producing cells in the CNS. Hortega also recognised microglia [19], as Nissl already did in 1899 [20] and named them the ‘true third element’, placing oligodendrocytes with astrocytes in the second element of the CNS. He stated that microglia originate from peripheral blood macrophages and that they can change from an inactive in to a phagocytic, active state in response to infection. Although Golgi showed in 1871 that processes of glial cells (i.e. astrocytes) contact blood vessels and concluded from this that glial cells provide nutritional fluids from capillaries to neurons [13], Cajal did not agree with this theory and proposed that glial cells (i.e. astrocytes, as oligodendrocytes and microglia were not identified yet) serve as insulation for the passage of nerve impulses [21]. He also considered the filling theory of Weigert, who stated that glial cells serve a passive role in filling up spaces around neurons [22]. Although Cajal also disagreed with this theory, Weigert’s idea has persisted a long time among scientists and is even under discussion today. Elements of all neurons reside in the CNS. However, many processes of neurons leave the CNS and enter the periphery nervous system or PNS to activate muscles or locate signals like touch, sound, smell or vision. Neurons are typically composed of a cell body, with a fine axon emerging from one pole and a set of dendrites from the opposing pole (see Figure 1.2). This standard idea about the shape of neurons comes from the studies of Purkyne. However, the neuron is the most polymorphic cell of the body. Many types of neurons differ in size, shape and function. Thus, it is difficult to define if a cell is a neuron by a single feature like shape or location. Neurons form networks in the CNS and the periphery by contacting other neurons via synapses, i.e. small gaps between a dendrite, axon or cell body of one neuron and similar structures of another neuron. Neurons communicate via chemical and electrical synapses (the latter reviewed in [23]), in a process known as synaptic transmission. The fundamental course of action triggering synaptic transmission is the action potential. This is a propagating electrical signal that is generated by depolarising the membrane potential of the plasma membrane of the neuron. When this action potential is generated, it passes through in the direction of synapses located in dendrites at the end of the axon. There it induces the fusion of synaptic vesicles filled with neurotransmitter with the plasma membrane. Subsequently, the neurotransmitter is released into the synapse, where it diffuses to the post-synaptic neuron and binds to its specific receptor. The action of the neurotransmitter can be excitatory (e.g. glutamate) or inhibitory (e.g. γ -aminobutyric acid (GABA)) meaning that the activity in the target neuron may either increase or decrease, respectively. For example a motor neuron that functionally connects the motor cortex to a muscle in the leg, may release excitatory neurotransmitters to contract or inhibitory neurotransmitters to relax the muscle. In addition, the released neurotransmitter may activate receptors on the membrane of the pre-synaptic neuron thereby preventing the release of neurotransmitters and generating a negative feedback mechanism. Although in 1871 Camillo Golgi already suggested that astrocytes may provide nutritional support to neurons, it took decades before it was established that astrocytes and other glial cells served not only as brain glue. As the field evolved, it became clear that glial cells serve on one hand as support cells, and, on the other hand, are essential for optimal neuronal function. The illustration in Figure 1.6 shows how the different glial cells are localised with respect to neurons in the spinal cord. Astrocytes are the most common glial cells in the brain and outnumber neurons by 1:10. These cells contain processes that contact blood vessels, and surround neurons and synapses. Astrocytes are coupled to each other by gap-junctions, which enables intercellular communication. Like neurons, astrocytes maintain a membrane potential that is sensitive to potassium ions. It is shown that astrocytes take up the excess of K + released by depolarised neurons, thereby maintaining a stable K + level in the extracellular space (ECS). This is important as K + in the ECS regulates transmitter release, cerebral blood flow, glucose metabolism and neuronal activity [24]. Astrocytes are also responsible for the uptake of neurotransmitters like glutamate, the most common excitatory neurotransmitter in the CNS, after its release by neurons. This is necessary as remaining glutamate may overstimulate the neuron causing neuronal damage. This phenomenon is called excitotoxicity. Uptake occurs by glutamate transporters located in the plasma membrane of the astrocyte. In astrocytes, glutamate is converted to glutamine and transported back to neurons where it is transformed to glutamate and used again. This recycling system is called the glutamate/glutamine cycle [25]. By taking up glutamate, astrocytes sense neuronal activation. This stimulates glucose uptake by astrocytes from the circulation by glucose transporters located in the plasma membrane of the processes that contact capillaries. Glucose is converted to lactate and transported to nearby neurons to serve as energy source [26]. Evidence is growing that astrocytes are also involved in plasticity and memory [27]. Oligodendrocytes are defined as the cells producing myelin sheaths that insulate CNS neuronal axons. In addition to myelinating oligodendrocytes, satellite and progenitor oligodendrocytes exist in the human CNS [28]. About the two latter types of oligodendrocytes, little is known. Myelinating oligodendrocytes however, have been investigated intensively. These cells produce sheaths of myelin (up to 1 mm wide) that wrap around axons of neurons in the CNS up to 40 times, thereby separating and insulating the axons. Myelination prevents transmembrane ion fluxes and thereby serves as an electrical insulator permitting rapid conduction of action potentials along the axon. The individual myelin sheaths are divided by nodes of Ranvier. Myelination of the neuronal axon increases the speed with which the generated action potential is able to pass through the axon, as membrane depolarisation is only required at the nodes of Ranvier. Myelin consists of two bilayers of plasma membrane, separated by a small amount of cytosol (cytoplasmic interface). The bilayers exist of lipids (70%) and proteins (30%), which is an inversion of the normal lipid-protein ratio in the cell body membrane of the oligodendrocyte that shows the normal 40-60% lipid-protein ratio. As myelin is in continuity with the cell body plasma membrane, a gradient must be formed [29] to accomplish this. Myelinating oligodendrocytes show a slow mitotic rate and have poor regenerative capacity. Therefore they are the most vulnerable glial cells. Damage to oligodendrocytes therefore leads to demyelination. As a single oligodendrocyte cell is able to produce 20-70 processes of myelin that all wrap around different axons, degeneration of a single oligodendrocyte leads to disappearance of myelin segments around different axons. Remyelination is possible but occurs slowly and is often incomplete [30]. Approximately 5-12% of the non-neuronal cells consist of microglia. These highly mobile cells can be found throughout the adult CNS, but are of non-CNS origin. During embryonic development myeloid progenitor cells (which are also the precursor cells for macrophages) enter the brain from the periphery and differentiate into microglia [31]. Thus, the microglial cell is the glial cell type that acts as the immune cell of the central nervous system. Normally, they exist in the CNS as quiescent cells, although recent investigations have demonstrated that ‘quiescent’ microglia exhibit active “immune surveillance” [32]. Upon injury of CNS tissue, microglial cells become activated. They change into macrophages, phagocytosing degenerating cells and debris and expressing a variety of hydrolytic enzymes. In addition cytokines and growth factors are synthesised and released. Schwann cells are the PNS-analogues of oligodendrocytes and therefore these cells are actually no component of the neuroglia cell types. They form myelin sheaths around axons of neurons outside the CNS. Schwann cells begin to form the myelin sheath in mammals during embryonic development and act by spiralling around the axon, sometimes with as many as a hundred revolutions. Unlike oligodendrocytes, myelinating Schwann cells provide insulation to only one axon. Since each Schwann cell can cover about a millimetre of the axon, hundreds and often thousands are required to completely cover an axon, as axons in the PNS reach up to 1 meter. The individual Schwann cells are, like oligodendrocytes, separated by nodes of Ranvier. Neurons located in different parts of the CNS show different vulnerability and sensitivity towards endogenous and exogenous stimuli. As a reaction on such a stimulus, the delicate balance between neuronal and non-neuronal cells may be disturbed and, as a consequence, physiologically and/or anatomically related neuronal systems progressively degenerate. This is a hallmark of neurodegenerative disorders. As many different neuronal systems are present in the CNS, neurodegenerative diseases display a heterogeneous group of disorders. As most types of neurons do not divide, neurogenesis does not occur in many parts of the brain, and a degenerated neuron will often not be replaced. As a consequence, lesions develop and progressively the functions carried out by the degenerating part of the brain deteriorate.Join ResearchGate to access over 30 million figures and 100 million publications – all in one place.Copy referenceCopy captionPublished in
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　　人Axis抑制蛋白2(AXIN2)ELISA检测试剂盒　　产品性状：盒装液体。　　人Axis抑制蛋白2(AXIN2)ELISA检测试剂盒提供免费检测服务，公司将根据实验工作量和难易程度，双方协定实验周期，保质保量完成委托实验，只收取试剂盒的费用，其他辅助试剂全部免费。　　运输条件：2-8℃低温运输，用干冰或者冰袋低温运输。　　待检样本：体液、血清、血浆、细胞培养上清液、尿液、组织匀浆、心房水标本等等。　　ELISA试剂盒检测范围：　　人、绵羊、小鼠、大鼠、猪、兔、山羊、牛、马、猪、其它动物细胞因子、植物细胞因子、骨代谢、细胞凋亡、激素内分泌、活性多肽、肝纤维化、自身抗体、血栓与止血、肿瘤、自身抗体科研Elisa检测试剂盒。　　ELISA试剂盒检测类型：双抗体夹心法测抗原、双抗原夹心法测抗体、间接法测抗体、竞争法测抗体、竞争法测抗原、捕获包被法测抗体、ABS-ELISA法。　　人Axis抑制蛋白2(AXIN2)ELISA检测试剂盒每次实验的标准曲线一般设7个不同浓度，加上空白孔，标准曲线一共需要8个孔。因此，一个48T试剂盒最多可以测定40个样本（不做重复且一次用完），一个96T试剂盒最多可以测定88个样本（不做重复且一次用完）。可以根据实际样本数量和实验计划选择合适的产品规格。　　操作注意事项：　　1.实验中不用的板条应立即放回包装袋中，密封保存，以免变质。　　2.试剂应按标签说明书储存，使用前恢复到室温。稀稀过后的标准品应丢弃，不可保存。　　3.使用一次性的吸头以免交叉污染，吸取终止液和底物A、B液时，避免使用带金属部分的加样器。　　4.不用的其它试剂应包装好或盖好。不同批号的试剂不要混用。保质前使用。　　5.洗涤酶标板时应充分拍干，不要将吸水纸直接放入酶标反应孔中吸水。　　6.使用干净的塑料容器配置洗涤液。使用前充分混匀试剂盒里的各种成份及样品。　　7.加入试剂的顺序应一致，以保证所有反应板孔温育的时间一样。　　8.按照说明书中标明的时间、加液的量及顺序进行温育操作。　　9.底物A应挥发，避免长时间打开盖子。底物B对光敏感，避免长时间暴露于光下。避免用手接触，有毒。实验完成后应立即读取OD值。　　"人Axis抑制蛋白2(AXIN2)ELISA检测试剂盒"的相关介绍与试剂盒　　K-(Pe)-No1-04808人神经元导向因子3(NAV3)ELISA试剂盒；英文名称：Human Neuron Navigator 3(NAV3)ELISA Kit　　K-(Pe)-No1-04150人细胞维甲酸结合蛋白2(CRABP2)ELISA试剂盒；英文名称：Human Cellular Retinoic Acid Binding Protein 2(CRABP2)ELISA Kit　　K-(Pe)-No1-06217人干扰素调节因子1(IRF1)ELISA试剂盒；英文名称：Human Interferon Regulatory Factor 1(IRF1)ELISA Kit　　K-(Pe)-No1-07689人Collybistin蛋白(CB)ELISA试剂盒；英文名称：Human Collybistin(CB)ELISA Kit　　K-(Pe)-No1-03078人c-fosELISA试剂盒；英文名称：Human c-fos ELISA Kit　　K-(Pe)-No1-02044人黑色素浓缩激素(MCH)ELISA试剂盒；英文名称：Human melanin concentrating hormone,MCH ELISA kit　　K-(Pe)-No1-05238人耐氧化性能蛋白1(OXR1)ELISA试剂盒；英文名称：Human Oxidation Resistance 1(OXR1)ELISA Kit　　K-(Pe)-No1-00339人牙骨质蛋白1(CEMP-1)ELISA试剂盒；英文名称：Human Cementum Protein 1,CEMP-1 ELISA Kit　　K-(Pe)-No1-04031人心肌肌动蛋白α1(ACTC1)ELISA试剂盒；英文名称：Human Actin Alpha 1, Cardiac Muscle(ACTC1)ELISA Kit　　K-(Pe)-No1-03632人早期B-细胞因子1(EBF1)ELISA试剂盒；英文名称：Human Early B-Cell Factor 1(EBF1)ELISA Kit　　K-(Pe)-No1-07125人X-转运蛋白3(Xtrp3)ELISA试剂盒；英文名称：Human X-Transporter protein 3(Xtrp3)ELISA Kit　　K-(Pe)-No1-01893人碱性成纤维细胞生长因子(bFGF)ELISA试剂盒；英文名称：Human basic fibroblast growth factor，bFGF ELISA Kit 　　K-(Pe)-No1-04831人神经肽Y受体Y2(NPY2R)ELISA试剂盒；英文名称：Human Neuropeptide Y Receptor Y2(NPY2R)ELISA Kit　　K-(Pe)-No1-01872人角化细胞内分泌因子(KAF)/双调蛋白(AR)ELISA试剂盒；英文名称：Human keratinocyte autocrine factor/Amphiregulin,KAF/AR ELISA Kit　　K-(Pe)-No1-07089人β-位淀粉样前体蛋白裂解酶2(βACE2)ELISA试剂盒；英文名称：Human Beta-Site APP Cleaving Enzyme 2(bACE2)ELISA Kit　　K-(Pe)-No1-05950人红细胞补体受体1(CR1)ELISA试剂盒；英文名称：Human Complement Receptor 1, Erythrocyte(CR1)ELISA Kit　　K-(Pe)-No1-05981人核纤层蛋白B2(LMNB2)ELISA试剂盒；英文名称：Human Lamin B2(LMNB2)ELISA Kit　　K-(Pe)-No1-04750人生长因子受体结合蛋白10(Grb10)ELISA试剂盒；英文名称：Human Growth Factor Receptor Bound Protein 10(Grb10)ELISA Kit　　K-(Pe)-No1-01517人柯萨奇病毒IgM(Cox V-IgM)ELISA试剂盒；英文名称：Human Coxsackie virus IgM，Cox V-IgM ELISA Kit　　K-(Pe)-No1-07548人H2A组蛋白家族成员V(H2AFV)ELISA试剂盒；英文名称：Human H2A Histone Family, Member V(H2AFV)ELISA Kit　　K-(Pe)-No1-02892人TGF-β诱导早期基因1(TIEG1)ELISA试剂盒；英文名称：Human TGF-beta-inducible early response gene-1,TIEG1 ELISA Kit　　K-(Pe)-No1-04305人外核苷酸焦磷酸酶/磷酸二酯酶6(ENPP6)ELISA试剂盒；英文名称：Human Ectonucleotide Pyrophosphatase/Phosphodiesterase 6(ENPP6)ELISA Kit　　K-(Pe)-No1-00806人丝裂原活化蛋白激酶(MAPK)ELISA试剂盒；英文名称：Human mitogen-activated　protein　kinases，MAPK ELISA Kit　　K-(Pe)-No1-04141人细胞周期素B3(CCNB3)ELISA试剂盒；英文名称：Human Cyclin B3(CCNB3)ELISA Kit　　K-(Pe)-No1-01928人脊髓灰质炎病毒抗原(PV)ELISA试剂盒；英文名称：Human Poliomyelitis Virus antigen ELISA Kit　　K-(Pe)-No1-04788人肾酶(RNLS)ELISA试剂盒；英文名称：Human Renalase(RNLS)ELISA Kit　　　　　　
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