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In 1860, the German anatomist Otto Friedrich Karl Deiters (1834-1863) described the basic structure of the nerve cell and identified two different protoplasmatic protrusions of the cell body that he termed as "axis cylinder," and "protoplasmatic processes," respectively axons and dendrites (see Illustration. Illustration of Axon).[1] Axons are the elongated portion of the neuron located in the center of the cell between the soma and axon terminals. In size, the axon may represent over 95% of the total volume of the neuron. Functionally, it carries electrical impulses and projects to synapses with dendrites or cell bodies of other neurons or with non-neuronal targets such as muscle fibers. Concerning length, the length of axons varies according to the function of the neuron. Considering the functional distinction between projection neurons and interneurons, cortical projection neurons (CPNs), also termed as pyramidal neurons and spinal cord projection neurons (dorsal horn neurons), usually have long axons (from several mm and up to 1 m). In contrast, interneurons, that work within local circuits, have a short axonal terminal (up to several mm). The longest axons of the human body are those that make up the sciatic nerve where the length can exceed one meter. Furthermore, compared to projecting neurons, interneurons usually have smaller soma, fewer organelles, and a reduced amount of cytoplasm (axoplasm). Histological observation of axon shows a cylindrical structure, but recent 3D electron microscopy studies demonstrated that probably axon has not the shape of a perfect cylinder.[2] The diameter is variable as it ranges between 1 and 25 micrometers. In squid, it reaches a diameter of 1 mm. The variation of the diameter has important functional implications since the speed of propagation of the impulse (i.e., action potential), besides being dependent on the presence of the myelin sheath, is directly proportional to the diameter of the axon. Moreover, they have demonstrated significant changes in the diameter along the single axon.[2] The axon is one of two types of protoplasmic protrusions of the neuronal soma. The other protrusion is the dendrites. Axons are distinguished from dendrites by several characteristics including: Shape. Dendrites are usually thin while axons typically maintain a constant radius

Histological observation of axon shows a cylindrical structure, but recent 3D electron microscopy studies demonstrated that probably axon has not the shape of a perfect cylinder.[2] The diameter is variable as it ranges between 1 and 25 micrometers. In squid, it reaches a diameter of 1 mm. The variation of the diameter has important functional implications since the speed of propagation of the impulse (i.e., action potential), besides being dependent on the presence of the myelin sheath, is directly proportional to the diameter of the axon. Moreover, they have demonstrated significant changes in the diameter along the single axon.[2] The axon is one of two types of protoplasmic protrusions of the neuronal soma. The other protrusion is the dendrites. Axons are distinguished from dendrites by several characteristics including: Shape. Dendrites are usually thin while axons typically maintain a constant radius Length. Dendrites are limited to a small region around the cell body while axons can be much longer Structure. Substantial structural differences exist between dendrites and axons. For example, only dendrites contain rough endoplasmic reticulum and ribosomes, and the structure of the cytoskeleton is different. Differences also affect the membrane as it contains mostly voltage-gated ion channels in axons, whereas ligand-gated ion channels are present, especially in dendrites. Functions. Dendrites usually receive signals, while axons typically transmit them. However, all these rules have exceptions. Furthermore, axons generate and transmit all-or-none action potential, whereas dendrites produce depolarizing (below the threshold of the action potential) or hyperpolarizing (lowering the resting membrane potential) graded potentials.

Functions. Dendrites usually receive signals, while axons typically transmit them. However, all these rules have exceptions. Furthermore, axons generate and transmit all-or-none action potential, whereas dendrites produce depolarizing (below the threshold of the action potential) or hyperpolarizing (lowering the resting membrane potential) graded potentials. Of note, although each neuron has only one axon, bifurcations that are branches of the main axon can be present. A collateral branch is an axonal protrusion over10 micrometers in length.[3] These collaterals provide modulation and regulation of the cell firing pattern and represent a feedback system for the neuronal activity. The terminal part of the axon and collaterals tapers progressively. These parts are called telodendron and continue with the synapse (synaptic knob or button) which represents the specialized structure that comes into contact with another neuron (soma, axon or dendrite), or muscle fiber. Axon extension and growth of new telodendrons (and synapses) are guided by several factors, including the nerve growth factor (NGF). The branching processes, in turn, play a role of fundamental importance in neuroplasticity, for instance, in cognitive processes such as memory and learning. Anatomically and based on the appearance of the protoplasmatic protrusions, neurons are classified into three groups: Multipolar neurons. They are the most common neurons; Shape: a single axon and many dendrites extending from the cell body. Localization: central nervous system (CNS) Unipolar (or pseudounipolar) neurons. Shape: a single short process that extends from the cell body and then splits into two branches in opposite directions; one branch travels to the peripheral nervous system (PNS) for the sensory reception, and the other to the CNS (central process). These neurons have no dendrites as the branched axon serving both functions. Localization: dorsal root ganglion and sensory ganglia of cranes nerves, and some mesencephalic nucleus Bipolar neurons. Shape: one axon and one dendrite that extend from the cell body in opposite directions. Localization: retinal cells and olfactory system

Unipolar (or pseudounipolar) neurons. Shape: a single short process that extends from the cell body and then splits into two branches in opposite directions; one branch travels to the peripheral nervous system (PNS) for the sensory reception, and the other to the CNS (central process). These neurons have no dendrites as the branched axon serving both functions. Localization: dorsal root ganglion and sensory ganglia of cranes nerves, and some mesencephalic nucleus Bipolar neurons. Shape: one axon and one dendrite that extend from the cell body in opposite directions. Localization: retinal cells and olfactory system Two notable features distinguish the axon from the soma (also referred to as perikaryon). First, no rough endoplasmic reticulum extends into the axon; secondly, the composition of the axonic membrane (axolemma) is fundamentally different from that of the somatic membrane. These structural differences translate into functional distinctions. In fact, since the absence of ribosomes does not allow protein synthesis, all axon proteins originate in the soma. Furthermore, the particular structure of the membrane due to the presence of specific protein channels allows information to travel along the course of the axon. Again, depending on the location within the body, these structures can be covered in sheaths of an insulating material known as myelin. Based on the presence or absence of the myelin sheath, axons are distinguishable into myelinated and non-myelinated axons. Myelin sheath

Two notable features distinguish the axon from the soma (also referred to as perikaryon). First, no rough endoplasmic reticulum extends into the axon; secondly, the composition of the axonic membrane (axolemma) is fundamentally different from that of the somatic membrane. These structural differences translate into functional distinctions. In fact, since the absence of ribosomes does not allow protein synthesis, all axon proteins originate in the soma. Furthermore, the particular structure of the membrane due to the presence of specific protein channels allows information to travel along the course of the axon. Again, depending on the location within the body, these structures can be covered in sheaths of an insulating material known as myelin. Based on the presence or absence of the myelin sheath, axons are distinguishable into myelinated and non-myelinated axons. Myelin sheath Myelin forms by the concentric wraps of the plasma membrane of neuroglia cells around the axon. These cells are the Schwann cells (or neurolemmocytes) in the PNS and oligodendrocytes in the CNS. As a general rule, oligodendrocytes myelinate multiple adjacent axons, while Schwann cells myelinate only one axon. In structural terms, the myelin sheath wraps the axons discontinuously as it is interrupted at regular intervals called Ranvier nodes (also termed as myelin sheath gaps), which represent the space between two consecutive Schwann cells and at which the axon is devoid of the sheath. In this way, employing the jump mechanism from one Ranvier node to the next, the propagation of the electrical signal is much faster than in the myelin sheathed axons. The cell membrane of Schwann cells is arranged around the axon, forming a double membrane structure (mesaxon), which elongates and wraps itself in a spiral, in concentric layers, around the axon itself. During this winding process, the cytoplasm of the Schwann cell is pushed towards the outside, while the surfaces of the contact membranes end up condensing, forming the lamellae of the myelin sheath. When the myelin sheath wraps around the axon, the mesaxon disappears by fusion of the cytoplasmic membranes in contact, except in correspondence with the innermost gyrus (internal mesaxon) and the outermost gyrus (external mesaxon or neurilemma) where there is a turn outermost rich in the cytoplasm. When the myelin sheath forms by oligodendrocytes (in PNS), the outermost gyrus reduces to a tongue and, in turn, although there is the internal mesaxon, the external one is not recognizable. Functionally, myelin represents an electrical insulator, allowing an increased speed of conduction along with an axon. It facilitates electrical transmission via saltatory conduction. Structurally, myelin is composed of approximately 80% of lipids (mostly cholesterol and variable amounts of cerebrosides and phospholipids) and 20% of proteins. However, depending on its location, myelin has a different composition as CNS myelin has more glycolipid and less phospholipid than PNS myelin.

Demyelination Demyelination is a destructive removal of myelin that induces a paramount impairment in impulse transmission. A demyelinated axon, indeed, transmits impulses up to 10 times slower than normal myelinated, whereas a complete stop of the transmission is also possible. Myelin and axonal degradation are observed in multiple sclerosis (MS). In this immune-mediated inflammatory disease, the inflammatory and demyelinating plaques are accompanied by perivenular macrophage, lymphocyte infiltration, and oligodendrocyte degradation. The observable clinical symptoms associated with the latter depend on the location of the affected neurons. The exponential downward trend of neurodegeneration development is complicated and could be related to the dysfunction of ion channels, calcium overload, synaptopathy, activation of apoptotic pathways, or glutamate-related excitotoxicity.[19] Other pathologies may induce immune-mediated myelin damage. Multifocal motor neuropathy (MMN), also known as multifocal motor neuropathy with conduction block (MMNCB), is a rare, acquired, motor neuropathy featuring progressive asymmetric weakness without sensory problems. It typically involves upper limbs more than the lower limbs. Concerning pathophysiology, pieces of evidence suggest that anti-ganglioside antibodies (anti-GM1) may be responsible for sodium and potassium channel dysfunction at the node of Ranvier of myelinated motor axons ('node-paranodopathy').[20] Axonal acute damage

Other pathologies may induce immune-mediated myelin damage. Multifocal motor neuropathy (MMN), also known as multifocal motor neuropathy with conduction block (MMNCB), is a rare, acquired, motor neuropathy featuring progressive asymmetric weakness without sensory problems. It typically involves upper limbs more than the lower limbs. Concerning pathophysiology, pieces of evidence suggest that anti-ganglioside antibodies (anti-GM1) may be responsible for sodium and potassium channel dysfunction at the node of Ranvier of myelinated motor axons ('node-paranodopathy').[20] Axonal acute damage Apart from MS, research focuses on understanding the mechanisms of axonal damage in acute and chronic pathologies. In the mid-nineteenth century, the British physiologist Augustus Volney Waller (1816-1870) showed that a full-thickness section of a nerve induces degeneration and reabsorption of its distal segment. The leading cause of this degeneration (Wallerian degeneration) is the interruption of axonal flow and the lack of ribosomes in the axon. The post-injury degenerative process has been subject to further dissection. In the case of a focal traumatic axonal lesion (e.g., due to spinal cord injury, SCI), the adjacent 400 to 600 micrometers of the axon on both sides of the lesion is involved in a rapid degenerative process (acute axonal degeneration). The molecular mechanisms comprise a cascade of events involving a rapid calcium influx into the axon, activation of calcium-dependent proteases (e.g., calpain and calcineurin), mitochondrial damage with the production of reactive oxygen species, alterations of neurofilaments with the fragmentation of microtubules, and impairment of axonal transport. The cascade culminates in the activation of autophagy. After 24 to 72 hours, the distal part of the axon is subject to Wallerian degeneration, which is mediated by the activation of nicotinamide mononucleotide adenylyltransferase (neuroprotective under physiological conditions) and is directed along the axon.[21]

Apart from MS, research focuses on understanding the mechanisms of axonal damage in acute and chronic pathologies. In the mid-nineteenth century, the British physiologist Augustus Volney Waller (1816-1870) showed that a full-thickness section of a nerve induces degeneration and reabsorption of its distal segment. The leading cause of this degeneration (Wallerian degeneration) is the interruption of axonal flow and the lack of ribosomes in the axon. The post-injury degenerative process has been subject to further dissection. In the case of a focal traumatic axonal lesion (e.g., due to spinal cord injury, SCI), the adjacent 400 to 600 micrometers of the axon on both sides of the lesion is involved in a rapid degenerative process (acute axonal degeneration). The molecular mechanisms comprise a cascade of events involving a rapid calcium influx into the axon, activation of calcium-dependent proteases (e.g., calpain and calcineurin), mitochondrial damage with the production of reactive oxygen species, alterations of neurofilaments with the fragmentation of microtubules, and impairment of axonal transport. The cascade culminates in the activation of autophagy. After 24 to 72 hours, the distal part of the axon is subject to Wallerian degeneration, which is mediated by the activation of nicotinamide mononucleotide adenylyltransferase (neuroprotective under physiological conditions) and is directed along the axon.[21] The traumatic axonal injury (TAI) is severe axonal mechanical damage due to the high rotational acceleration of the brain.[22] Although its pathophysiology is complex, it seems that the damage is firstly produced by mechanically break involving axonal microtubules. This mechanical stretch reverberates on the axonal structure (undulations and breaks) and induces direct membrane mechanoporation with calcium influx that activates several injurious pathways such as the caspase-mediated proteolysis and the cytokine-mediated microglia recruitment. The effect is the impairment of axonal transport and the accumulation of transported proteins in varicose swellings.[23] Chemotherapy-induced peripheral neuropathy

The traumatic axonal injury (TAI) is severe axonal mechanical damage due to the high rotational acceleration of the brain.[22] Although its pathophysiology is complex, it seems that the damage is firstly produced by mechanically break involving axonal microtubules. This mechanical stretch reverberates on the axonal structure (undulations and breaks) and induces direct membrane mechanoporation with calcium influx that activates several injurious pathways such as the caspase-mediated proteolysis and the cytokine-mediated microglia recruitment. The effect is the impairment of axonal transport and the accumulation of transported proteins in varicose swellings.[23] Chemotherapy-induced peripheral neuropathy The neurotoxicity, due to the anticancer drugs, also referred to as chemotherapy-induced peripheral neuropathy (CIPN), has multiple mechanisms involving axon and other neuronal compartments.[24] For example, proteasome inhibitors (e.g., bortezomib) provoke pathological changes in Schwann cells and myelin and, in turn, axonal degeneration.[25] Again, microtubule alterations and impairment of axonal transport are primarily involved in dose-dependent taxane neurotoxicity, whereas calcium-related neurotoxicity has involvement in the pathogenesis of oxaliplatin-induced CIPN.[26] Neurodegenerative processes In neurodegenerative processes such as Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS), the axonal compartment degenerates more slowly over longer time-periods. Research has also described the features of focal axonal degeneration. They manifest themselves as district morphological alterations due to damage of axonal transport, in turn, secondary to harmful processes affecting mitochondria and other support structures. Interestingly, these processes, within certain limits, can be reversible. Furthermore, several studies have focused on alterations of bi-directional axonal transport and the pathogenetic role of microtubule alterations in degenerative diseases.[27]