Disruption Of Axonal Transport Research Articles

Characterizing immune-mediated neuronal microtubule destabilization and axonal transport defects in a mouse model of optic neuritis

Abstract Multiple sclerosis (MS) is a central nervous system autoimmune disease that often presents with inflammation of the optic nerve, optic neuritis (ON). The mechanisms of neuronal damage in MS and ON are unknown. In vitro studies modeling MS neurodegeneration demonstrated that cytolytic lymphocytes drive microtubule destabilization in human induced pluripotent stem cell-derived spinal motor neurons. Microtubules are essential for axonal transport, a key function for neuron health. We hypothesize that immune-mediated neuronal microtubule destabilization drives development of ON through disruption of axonal transport. MOG35-55 T cell receptor transgenic mice were used as a model of ON. The non-invasive ophthalmologic technique optical coherence tomography (OCT) allows for confirmation of symptomatic ON. Using OCT, increasing severity of progressive ON was observed over 5 months. To examine transport efficiency, cholera toxin subunit B (CTB), an axonal transport tracer, was injected into the eyes of mice with ON. Optic nerves were collected and stained for β3-tubulin, a marker of microtubules, and imaged by immunofluorescence. Preliminary data found decreased β3-tubulin staining and markedly reduced CTB transport in the presence of immune cell infiltration in mice with ON. These data confirm that OCT can be used to monitor ON progression and provide evidence that immune-mediated neuronal microtubule destabilization causes axonal transport deficits that underly ON development.

Trace Elements in Alzheimer's Disease and Dementia: The Current State of Knowledge.

Changes in trace element concentrations are being wildly considered when it comes to neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. This study aims to present the role that trace elements play in the central nervous system. Moreover, we reviewed the mechanisms involved in their neurotoxicity. Low zinc concentrations, as well as high levels of copper, manganese, and iron, activate the signalling pathways of the inflammatory, oxidative and nitrosative stress response. Neurodegeneration occurs due to the association between metals and proteins, which is then followed by aggregate formation, mitochondrial disorder, and, ultimately, cell death. In Alzheimer's disease, low Zn levels suppress the neurotoxicity induced by β-amyloid through the selective precipitation of aggregation intermediates. High concentrations of copper, iron and manganese cause the aggregation of intracellular α-synuclein, which results in synaptic dysfunction and axonal transport disruption. Parkinson's disease is caused by the accumulation of Fe in the midbrain dopaminergic nucleus, and the pathogenesis of multiple sclerosis derives from Zn deficiency, leading to an imbalance between T cell functions. Aluminium disturbs the homeostasis of other metals through a rise in the production of oxygen reactive forms, which then leads to cellular death. Selenium, in association with iron, plays a distinct role in the process of ferroptosis. Outlining the influence that metals have on oxidoreduction processes is crucial to recognising the pathophysiology of neurodegenerative diseases and may provide possible new methods for both their avoidance and therapy.

Bearded capuchin monkeys as a model for Alzheimer's disease.

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread β-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of β-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Current potential pathogenic mechanisms of copper-zinc superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease which damages upper and lower motor neurons (UMN and LMN) innervating the muscles of the trunk, extremities, head, neck and face in cerebrum, brain stem and spinal cord, which results in the progressive weakness, atrophy and fasciculation of muscle innervated by the related UMN and LMN, accompanying with the pathological signs leaded by the cortical spinal lateral tract lesion. The pathogenesis about ALS is not fully understood, and no specific drugs are available to cure and prevent the progression of this disease at present. In this review, we reviewed the structure and associated functions of copper-zinc superoxide dismutase 1 (SOD1), discuss why SOD1 is crucial to the pathogenesis of ALS, and outline the pathogenic mechanisms of SOD1 in ALS that have been identified at recent years, including glutamate-related excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, axonal transport disruption, prion-like propagation, and the non-cytologic toxicity of glial cells. This review will help us to deeply understand the current progression in this field of SOD1 pathogenic mechanisms in ALS.

Deregulated mitochondrial quality control, the heel of Achilles in elucidating the role of autophagy in SARM1-mediated axon degeneration.

Autophagic dysfunction in neurodegenerative diseases is being extensively studied, yet the exact mechanism of macroautophagy/autophagy in axon degeneration is still elusive. A recent study by Kim etal. links autophagic stress to the sterile α and toll/interleukin 1 receptor motif containing protein 1 (SARM1)-dependent core axonal degeneration program, providing a new insight into the role of autophagy in axon degeneration. In the classical Wallerian axon degeneration model of axotomy, disruption of axonal transport destroys the coordinated activity of pro-survival and pro-degenerative factors in the axoplasm and activates the NADase activity of SARM1, thus triggering the axonal self-destruction program. However, the mechanism for SARM1 activation in the chronic neurodegenerative disorders is more complex. Mitochondrial defects and oxidative stress contribute to the activation of SARM1, while mitophagy can inhibit mitochondrial dysfunction and promote the clearance of SARM1 on mitochondria, thus protecting against neuronal degeneration. Therefore, in-depth elucidation of the underlying mechanisms of mitophagy during axonal degeneration can help develop promising strategies for the prevention and treatment of various neurodegenerative disorders.

Identifying the Phenotypes of Diffuse Axonal Injury Following Traumatic Brain Injury.

Diffuse axonal injury (DAI) is a significant feature of traumatic brain injury (TBI) across all injury severities and is driven by the primary mechanical insult and secondary biochemical injury phases. Axons comprise an outer cell membrane, the axolemma which is anchored to the cytoskeletal network with spectrin tetramers and actin rings. Neurofilaments act as space-filling structural polymers that surround the central core of microtubules, which facilitate axonal transport. TBI has differential effects on these cytoskeletal components, with axons in the same white matter tract showing a range of different cytoskeletal and axolemma alterations with different patterns of temporal evolution. These require different antibodies for detection in post-mortem tissue. Here, a comprehensive discussion of the evolution of axonal injury within different cytoskeletal elements is provided, alongside the most appropriate methods of detection and their temporal profiles. Accumulation of amyloid precursor protein (APP) as a result of disruption of axonal transport due to microtubule failure remains the most sensitive marker of axonal injury, both acutely and chronically. However, a subset of injured axons demonstrate different pathology, which cannot be detected via APP immunoreactivity, including degradation of spectrin and alterations in neurofilaments. Furthermore, recent work has highlighted the node of Ranvier and the axon initial segment as particularly vulnerable sites to axonal injury, with loss of sodium channels persisting beyond the acute phase post-injury in axons without APP pathology. Given the heterogenous response of axons to TBI, further characterization is required in the chronic phase to understand how axonal injury evolves temporally, which may help inform pharmacological interventions.

Treponema denticola Has the Potential to Cause Neurodegeneration in the Midbrain via the Periodontal Route of Infection-Narrative Review.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common example of dementia. The neuropathological features of AD are the abnormal deposition of extracellular amyloid-β (Aβ) and intraneuronal neurofibrillary tangles with hyperphosphorylated tau protein. It is recognized that AD starts in the frontal cerebral cortex, and then it progresses to the entorhinal cortex, the hippocampus, and the rest of the brain. However, some studies on animals suggest that AD could also progress in the reverse order starting from the midbrain and then spreading to the frontal cortex. Spirochetes are neurotrophic: From a peripheral route of infection, they can reach the brain via the midbrain. Their direct and indirect effect via the interaction of their virulence factors and the microglia potentially leads to the host peripheral nerve, the midbrain (especially the locus coeruleus), and cortical damage. On this basis, this review aims to discuss the hypothesis of the ability of Treponema denticola to damage the peripheral axons in the periodontal ligament, to evade the complemental pathway and microglial immune response, to determine the cytoskeletal impairment and therefore causing the axonal transport disruption, an altered mitochondrial migration and the consequent neuronal apoptosis. Further insights about the central neurodegeneration mechanism and Treponema denticola's resistance to the immune response when aggregated in biofilm and its quorum sensing are suggested as a pathogenetic model for the advanced stages of AD.

Disruption of axonal transport in neurodegeneration.

Neurons are markedly compartmentalized, which makes them reliant on axonal transport to maintain their health. Axonal transport is important for anterograde delivery of newly synthesized macromolecules and organelles from the cell body to the synapse and for the retrograde delivery of signaling endosomes and autophagosomes for degradation. Dysregulation of axonal transport occurs early in neurodegenerative diseases and plays a key role in axonal degeneration. Here, we provide an overview of mechanisms for regulation of axonal transport; discuss how these mechanisms are disrupted in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, hereditary spastic paraplegia, amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease; and discuss therapeutic approaches targeting axonal transport.

Probiotics for Neurodegenerative Diseases: A Systemic Review.

Neurodegenerative disorders (ND) are a group of conditions that affect the neurons in the brain and spinal cord, leading to their degeneration and eventually causing the loss of function in the affected areas. These disorders can be caused by a range of factors, including genetics, environmental factors, and lifestyle choices. Major pathological signs of these diseases are protein misfolding, proteosomal dysfunction, aggregation, inadequate degradation, oxidative stress, free radical formation, mitochondrial dysfunctions, impaired bioenergetics, DNA damage, fragmentation of Golgi apparatus neurons, disruption of axonal transport, dysfunction of neurotrophins (NTFs), neuroinflammatory or neuroimmune processes, and neurohumoral symptoms. According to recent studies, defects or imbalances in gut microbiota can directly lead to neurological disorders through the gut-brain axis. Probiotics in ND are recommended to prevent cognitive dysfunction, which is a major symptom of these diseases. Many in vivo and clinical trials have revealed that probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, and Lactobacillus casei, etc.) are effective candidates against the progression of ND. It has been proven that the inflammatory process and oxidative stress can be modulated by modifying the gut microbiota with the help of probiotics. As a result, this study provides an overview of the available data, bacterial variety, gut-brain axis defects, and probiotics' mode of action in averting ND. A literature search on particular sites, including PubMed, Nature, and Springer Link, has identified articles that might be pertinent to this subject. The search contains the following few groups of terms: (1) Neurodegenerative disorders and Probiotics OR (2) Probiotics and Neurodegenerative disorders. The outcomes of this study aid in elucidating the relationship between the effects of probiotics on different neurodegenerative disorders. This systematic review will assist in discovering new treatments in the future, as probiotics are generally safe and cause mild side effects in some cases in the human body.

Phosphomimetics at Ser199/Ser202/Thr205 in Tau Impairs Axonal Transport in Rat Hippocampal Neurons.

Our understanding of the biological functions of the tau protein now includes its role as a scaffolding protein involved in signaling regulation, which also has implications for tau-mediated dysfunction and degeneration in Alzheimer's disease and other tauopathies. Recently, we found that pseudophosphorylation at sites linked to the pathology-associated AT8 phosphoepitope of tau disrupts normal fast axonal transport through a protein phosphatase 1 (PP1)-dependent pathway in squid axoplasm. Activation of the pathway and the resulting transport deficits required tau's N-terminal phosphatase-activating domain (PAD) and PP1 but the connection between tau and PP1 was not well defined. Here, we studied functional interactions between tau and PP1 isoforms and their effects on axonal transport in mammalian neurons. First, we found that wild-type tau interacted with PP1α and PP1γ primarily through its microtubule-binding repeat domain. Pseudophosphorylation of tau at S199/S202/T205 (psTau) increased PAD exposure, enhanced interactions with PP1γ, and increased active PP1γ levels in mammalian cells. Expression of psTau also significantly impaired axonal transport in primary rat hippocampal neurons. Deletion of PAD in psTau significantly reduced the interaction with PP1γ, eliminated increases of active PP1γ levels, and rescued axonal transport impairment in neurons. These data suggest that a functional consequence of phosphorylation within S199-T205 in tau, which occurs in AD and several other tauopathies, may be aberrant interaction with and activation of PP1γ and subsequent axonal transport disruption in a PAD-dependent fashion.

Clinical-Pathological Study on Expressions β-APP, GFAP, NFL, Spectrin II, CD68 to Verify Diffuse Axonal Injury Diagnosis, Grade and Survival Interval

Traumatic brain injury (TBI) is one of the leading causes of death worldwide, particularly in young people. Diffuse axonal injuries (DAI) are the result of strong rotational and translational forces on the brain parenchyma, leading to cerebral oedema and neuronal death. DAI is typically characterized by coma without focal lesions at presentation and is defined by localized axonal damage in multiple regions of the brain parenchyma, often causing impairment of cognitive and neuro-vegetative function. Following TBI, axonal degeneration has been identified as a progressive process that begins with the disruption of axonal transport, leading subsequently to axonal swelling, axonal ballooning, axonal retraction bulges, secondary disconnection and Wallerian degeneration. The objective of this paper is to report on a series of patients who have suffered fatal traumatic brain injury, in order to verify neurological outcomes in dynamics, relative to the time of injury, using antibodies for neurofilament (NFL), spectrin II, beta-amyloid (β-APP), glial fibrillary acidic protein (GFAP) and cluster of differentiation 68 (CD68). From the studied cases, a total of 50 cases were chosen, which formed two study groups. The first study group comprises 30 cases divided according to survival interval. The control group comprises 20 cases with no history of traumatic brain injury. Cardiovascular disease and history of stroke, cases suffering from loss of vital functions, a post-traumatic survival time of less than 15 min, autolysis and putrefaction were established as criteria for exclusion. Based on their expression, we tested for diagnosis and degree of DAI as a strong predictor of mortality. Immunoreactivity was significantly increased in the DAI group compared to the control group. The earliest changes were recorded for GFAP and CD68 immunolabeling, followed by β-APP, spectrin II and NFM. The most intense changes in immunostaining were recorded for spectrin II. Comparative analysis of brain apoptosis, reactive astrocytosis and inflammatory reaction using specific immunohistochemical markers can provide important information on diagnosis of DAI and prognosis, and may elucidate the timing of the traumatic event in traumatic brain injury.

Optic Pathway Edema Mimicking Multifocal/Multicentric Glioblastoma Multiforme: A Case Report and Review

Multifocal/multicentric glioblastoma is a rare variant of glioblastoma that carries a worse prognosis than singular glioblastoma. We report a case of optic nerve edema mimicking multifocal/multicentric glioblastoma in a 24-year-old man. It was suspected that the pathophysiology of edema was due to mechanical compression of the optic nerve causing axonal transport disruption as well as vasogenic edema from inflammatory response to the tumor.

Protective Role of Capsaicin in Neurological Disorders: An Overview.

Different pathological conditions that begin with slow and progressive deformations, cause irreversible affliction by producing loss of neurons and synapses. Commonly it is referred to as 'protein misfolding' diseases or proteinopathies and comprises the latest definition of neurological disorders (ND). Protein misfolding dynamics, proteasomal dysfunction, aggregation, defective degradation, oxidative stress, free radical formation, mitochondrial dysfunctions, impaired bioenergetics, DNA damage, neuronal Golgi apparatus fragmentation, axonal transport disruption, Neurotrophins (NTFs) dysfunction, neuroinflammatory or neuroimmune processes, and neurohumoral changes are the several mechanisms that embark the pathogenesis of ND. Capsaicin (8-Methyl-N-vanillyl-6-nonenamide) one of the major phenolic components in chili peppers (Capsicum) distinctively triggers the unmyelinated C-fiber and acts on Transient Receptor Potential Vanilloid-1, which is a Ca2+ permeable, non-selective cation channel. Several studies have shown the neuroprotective role of capsaicin against oxidative damage, behavioral impairment, with 6-hydroxydopamine (6-OHDA) induced Parkinson's disease, pentylenetetrazol-induced seizures, global cerebral ischemia, and streptozotocin-induced Alzheimer's disease. Based on these lines of evidence, capsaicin can be considered as a potential constituent to develop suitable neuro-pharmacotherapeutics for the management and treatment of ND. Furthermore, exploring newer horizons and carrying out proper clinical trials would help to bring out the promising effects of capsaicin to be recommended as a neuroprotectant.

Screening the Efficacy of Melatonin on Neurodegeneration Mediated by Endoplasmic Reticulum Stress, Inflammation, and Oxidative Damage.

Neurodegeneration may be defined as a clinical condition wherein neurons gradually lose their structural integrity, viability, and functional abilities and the damage inflicted upon the neurons is often irreversible. The various mechanisms that have been observed to contribute to neurodegeneration include aggregation and accumulation of misfolded proteins, impaired autophagy, oxidative damage, neuroinflammation, mitochondrial defects, increased SUMOylation of proteins, impaired unfolded protein response (UPR) pathways, and disruption of axonal transport. Melatonin, a neurohormone, is involved in a variety of functions including scavenging free radicals, synchronizing the circadian rhythm, and mitigating immune response. Melatonin has shown to modulate the UPR pathway, antioxidant pathway through Nrf2 and inflammatory pathway through NFκB. The study aims to determine the efficacy of melatonin on neurodegeneration mediated by endoplasmic reticulum (ER) stress, inflammation, and oxidative damage through in silico approaches. The molecular targets chosen were ATF6, XBP1, PERK, Nrf2, and NFκB and they were docked against melatonin. Melatonin showed to have binding energy with ATF6 as - 4.8kJ, with PERK as - 3.2kJ, with XBP1 as - 4.8kJ, with Nrf2 as - 4.5kJ, and with that of NFκB as - 4.2kJ, which implies it interacts well with them. Additionally various physiochemical analyses such as absorption, distribution, metabolism, excretion (ADME) were also carried out. Those analyses revealed that it has an optimal log P of about 1.98, optimal log S of - 2.34, is BBB permeant, has high GI absorption, is not a P-Gp substrate, has a TPSA of 54.12, has a molecular weight of 232.28, and has about 4 rotatable bonds. Also, it showed a bioactivity score of 0.06 for GPCR which implies that it is most likely to exert its function by binding GPCR. The findings imply that melatonin not only shows excellent interactions with the targets but also possesses drug-like physicochemical properties that makes it a valuable choice for the treatment of neurodegenerative disorders.

Traumatic Brain Injury: Mechanisms of Glial Response.

Traumatic brain injury (TBI) is a heterogeneous disorder that involves brain damage due to external forces. TBI is the main factor of death and morbidity in young males with a high incidence worldwide. TBI causes central nervous system (CNS) damage under a variety of mechanisms, including synaptic dysfunction, protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Glial cells comprise most cells in CNS, which are mediators in the brain’s response to TBI. In the CNS are present astrocytes, microglia, oligodendrocytes, and polydendrocytes (NG2 cells). Astrocytes play critical roles in brain’s ion and water homeostasis, energy metabolism, blood-brain barrier, and immune response. In response to TBI, astrocytes change their morphology and protein expression. Microglia are the primary immune cells in the CNS with phagocytic activity. After TBI, microglia also change their morphology and release both pro and anti-inflammatory mediators. Oligodendrocytes are the myelin producers of the CNS, promoting axonal support. TBI causes oligodendrocyte apoptosis, demyelination, and axonal transport disruption. There are also various interactions between these glial cells and neurons in response to TBI that contribute to the pathophysiology of TBI. In this review, we summarize several glial hallmarks relevant for understanding the brain injury and neuronal damage under TBI conditions.

Amyloidogenic Processing of Amyloid Precursor Protein Drives Stretch-Induced Disruption of Axonal Transport in hiPSC-Derived Neurons.

Traumatic brain injury (TBI) results in disrupted brain function following impact from an external force and is a risk factor for sporadic Alzheimer's disease (AD). Although neurologic symptoms triggered by mild traumatic brain injuries (mTBI), the most common form of TBI, typically resolve rapidly, even an isolated mTBI event can increase the risk to develop AD. Aberrant accumulation of amyloid β peptide (Aβ), a cleaved fragment of amyloid precursor protein (APP), is a key pathologic outcome designating the progression of AD following mTBI and has also been linked to impaired axonal transport. However, relationships among mTBI, amyloidogenesis, and axonal transport remain unclear, in part because of the dearth of human models to study the neuronal response following mTBI. Here, we implemented a custom-microfabricated device to deform neurons derived from human-induced pluripotent stem cells, derived from a cognitively unimpaired male individual, to mimic the mild stretch experienced by neurons during mTBI. Although no cell lethality or cytoskeletal disruptions were observed, mild stretch was sufficient to stimulate rapid amyloidogenic processing of APP. This processing led to abrupt cessation of APP axonal transport and progressive formation of aberrant axonal accumulations that contained APP, its processing machinery, and amyloidogenic fragments. Consistent with this sequence of events, stretch-induced defects were abrogated by reducing amyloidogenesis either pharmacologically or genetically. In sum, we have uncovered a novel and manipulable stretch-induced amyloidogenic pathway directly responsible for APP axonal transport dysregulation. Our findings may help to understand and ultimately mitigate the risk of developing AD following mTBI.SIGNIFICANCE STATEMENT Mild traumatic brain injury is a risk factor for sporadic Alzheimer's disease (AD). Increased amyloid β peptide generation after injury may drive this risk. Here, by using a custom-built device to impose mild stretch to human neurons, we found that stretch triggers amyloid precursor protein (APP) cleavage, and thus amyloid β peptide generation, consequently disrupting APP axonal transport. Compellingly, protecting APP from cleavage was sufficient to spare axonal transport dysregulation and the consequent aberrant axonal accumulation of APP. Supporting such protective mechanism, the expression of the AD-protective APPA673T genetic variant conferred protection against stretch-induced APP axonal transport phenotypes. Our data reveal potential subcellular pathways contributing to the development of AD-associated phenotypes following mild traumatic brain injury, and putative strategies for intervening in these pathways.

Intranasal Paclitaxel Alters Alzheimer's Disease Phenotypic Features in 3xTg-AD Mice.

Microtubule stabilizing drugs, commonly used as anti-cancer therapeutics, have been proposed for treatment of Alzheimer's disease (AD); however, many do not cross the blood-brain barrier. This research investigated if paclitaxel (PTX) delivered via the intranasal (IN) route could alter the phenotypic progression of AD in 3xTg-AD mice. We administered intranasal PTX in 3XTg-AD mice (3xTg-AD n = 15, 10 weeks and n = 10, 44 weeks, PTX: 0.6 mg/kg or 0.9%saline (SAL)) at 2-week intervals. After treatment, 3XTg-AD mice underwent manganese-enhanced magnetic resonance imaging to measure in vivo axonal transport. In a separate 3XTg-AD cohort, PTX-treated mice were tested in a radial water tread maze at 52 weeks of age after four treatments, and at 72 weeks of age, anxiety was assessed by an elevated-plus maze after 14 total treatments. PTX increased axonal transport rates in treated 3XTg-AD compared to controls (p≤0.003). Further investigation using an in vitro neuron model of Aβ-induced axonal transport disruption confirmed PTX prevented axonal transport deficits. Confocal microscopy after treatment found fewer phospho-tau containing neurons (5.25±3.8 versus 8.33±2.5, p < 0.04) in the CA1, altered microglia, and reduced reactive astrocytes. PTX improved performance of 3xTg-AD on the water tread maze compared to controls and not significantly different from WT (Day 5, 143.8±43 versus 91.5±77s and Day 12, 138.3±52 versus 107.7±75s for SAL versus PTX). Elevated plus maze revealed that PTX-treated 3xTg-AD mice spent more time exploring open arms (Open arm 129.1±80 versus 20.9±31s for PTX versus SAL, p≤0.05). Taken collectively, these findings indicate that intranasal-administered microtubule-stabilizing drugs may offer a potential therapeutic option for treating AD.

A Review of Traumatic Axonal Injury

Traumatic brain injury is a major cause of mortality and neurological disability worldwide and varies according to its cause, pathogenesis, severity and clinical outcome. This review summarizes a significant aspect of diffuse brain injuries – traumatic axonal injury – important cause of severe disability and vegetative state. Traumatic axonal injury is a type of traumatic brain injury caused by blunt head trauma. It is defined both clinically (immediate and prolonged unconsciousness, characteristically in the absence of space-occupying lesions) and pathologically (widespread and diffuse damage of axons). Following traumatic brain injury, progressive axonal degeneration starts with disruption of axonal transport, axonal swelling, secondary axonal disconnection and Wallerian degeneration, respectively. However, traumatic axonal injury is difficult to define clinically, it should be considered in patients with Glasgow coma score &lt; 8 for more than six hours after trauma and diffuse tensor imaging and sensitivity-weighted imaging MRI sequences are highly sensitive in its diagnosis. Glasgow coma score at the time of presentation, location and severity of axonal damage are prognostic factors for clinical outcome.

Acupuncture for Paclitaxel-Induced Peripheral Neuropathy: A Review of Clinical and Basic Studies.

Paclitaxel-induced peripheral neuropathy (PIPN) is a common and intractable side effect of the conventional chemotherapeutic agent paclitaxel. Acupuncture has been reported as an effective alternative therapy in treatment of PIPN in both basic studies and clinical trials. However, there is a lack of comprehensive surveys to summarize the action of acupuncture in management of PIPN. In this review, we briefly demonstrate the basic pathology of PIPN, which includes the activation of ion channels, mitochondrial dysfunction, disruption of axonal transport and also neuro-inflammatory involvement. Meanwhile, we review both the clinical and basic studies as an emphasis to give a general overview of the therapeutic effect of acupuncture against PIPN. Finally, we summarize the current known mechanisms underlying the action of acupuncture against PIPN mainly at peripheral and spinal levels, which include various neurotransmitters, multiple receptors, different types of enzymes and molecules. In conclusion, acupuncture could be considered as a potential alternative therapy in treatment of PIPN, and further clinical and experimental studies are called for in the future.

SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate.

Loss-of-function mutations in sorting nexin 14 (SNX14) cause autosomal recessive spinocerebellar ataxia 20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of high-energy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggested valproate as a potential therapeutic agent.