Axonal Disruption Research Articles

Unraveling the interplay of kinesin-1, tau, and microtubules in neurodegeneration associated with Alzheimer’s disease

Alzheimer’s disease (AD) is marked by the gradual and age-related deterioration of nerve cells in the central nervous system. The histopathological features observed in the brain affected by AD are the aberrant buildup of extracellular and intracellular amyloid-β and the formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Axonal transport is a fundamental process for cargo movement along axons and relies on molecular motors like kinesins and dyneins. Kinesin’s responsibility for transporting crucial cargo within neurons implicates its dysfunction in the impaired axonal transport observed in AD. Impaired axonal transport and dysfunction of molecular motor proteins, along with dysregulated signaling pathways, contribute significantly to synaptic impairment and cognitive decline in AD. Dysregulation in tau, a microtubule-associated protein, emerges as a central player, destabilizing microtubules and disrupting the transport of kinesin-1. Kinesin-1 superfamily members, including kinesin family members 5A, 5B, and 5C, and the kinesin light chain, are intricately linked to AD pathology. However, inconsistencies in the abundance of kinesin family members in AD patients underline the necessity for further exploration into the mechanistic impact of these motor proteins on neurodegeneration and axonal transport disruptions across a spectrum of neurological conditions. This review underscores the significance of kinesin-1’s anterograde transport in AD. It emphasizes the need for investigations into the underlying mechanisms of the impact of motor protein across various neurological conditions. Despite current limitations in scientific literature, our study advocates for targeting kinesin and autophagy dysfunctions as promising avenues for novel therapeutic interventions and diagnostics in AD.

Torsion-Induced Traumatic Optic Neuropathy (TITON): A Physiologically Relevant Animal Model of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is a common cause of irreversible blindness following head injury. TON is characterized by axon damage in the optic nerve followed by retinal ganglion cell death in the days and weeks following injury. At present, no therapeutic or surgical approach has been found to offer any benefit beyond observation alone. This is due in part to the lack of translational animal models suitable for understanding mechanisms and evaluating candidate treatments. In this study, we developed a rat model of TON in which the eye is rapidly rotated, inflicting mechanical stress on the optic nerve and leading to significant visual deficits. These functional deficits were thoroughly characterized up to one week after injury using electrophysiology and immunohistochemistry. The photopic negative response (PhNR) of the light adapted full field electroretinogram (LA ffERG) was significantly altered following injury. This correlated with increased biomarkers of retinal stress, axon disruption, and ganglion cell death. Together, this evidence suggests the utility of our model for mimicking clinically relevant TON and that the PhNR may be an early diagnostic for TON. We also found indirect evidence that ketamine, which was used for anesthesia, may ameliorate TON. Future studies will utilize this animal model for evaluation of candidate treatments.

Advancements and mechanisms of stem cell-based therapies for spinal cord injury in animals.

Spinal cord injury (SCI) is a neurodegenerative disorder of the central nervous system (CNS) that can lead to permanent loss of sensation and voluntary movement beyond the affected area. Extensive preclinical and clinical trials have been conducted to evaluate the safety and effectiveness of stem cells for the treatment of various CNS diseases or disorders, including SCI. However, several challenges hinder nerve cell regeneration in the injured spinal cord, such as extensive cell loss, limited neural cell regeneration capacity, axonal disruption, and the presence of growth-inhibiting molecules, particularly astroglial scarring or glial scars at the injury site in chronic cases. These obstacles pose significant challenges for physicians in restoring normal motor and sensory nerve function in both humans and animals following SCI. This review focuses on SCI pathogenesis, the mechanisms underlying the therapeutic potential of Mesenchymal Stem Cells (MSCs) in SCI, and the potential of stem cell-based therapies as promising avenues for treatment. This review article also included relevant preclinical and clinical data from animal studies.

Exosomal miR-17-92 Cluster from BMSCs Alleviates Apoptosis and Inflammation in Spinal Cord Injury.

Spinal cord injury (SCI) involves neuronal apoptosis and axonal disruption, leading to severe motor dysfunction. Studies indicate that exosomes transport microRNAs (miRNAs) and play a crucial role in intercellular communication. This study aimed to explore whether the bone marrow mesenchymal stem cell (BMSCs)-exosomal miR-17-92 cluster can protect against SCI and to explain the underlying mechanisms. In vivo and in vitro SCI models were established and treated with control exosomes (con-exo) or exosomes derived from BMSCs transfected with miR-17-92 cluster plasmid (miR-17-92-exo). Rat BMSCs were isolated and positive markers were identified by flow cytometry. BMSC-derived exosomes were extracted and verified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. The expression of the miR-17-92 cluster was validated by quantitative reverse transcription PCR (qRT-PCR). Spinal cord function, histopathological changes, apoptotic cells, and inflammatory cytokines release in spinal cord tissues were assessed using the Basso-Beattie-Bresnahan (BBB) score, hematoxylin and eosin (HE) staining, terminal deoxynucleotide transferase (TdT)-mediated dUTPnick-endlabeling(TUNEL)staining, enzyme-linkedimmunosorbentassay(ELISA), and qRT-PCR. In PC12 cells, cell proliferation, apoptosis, apoptosis-related proteins cleaved-Caspase3 expression, and inflammatory factors secretion were analyzed using a cell counting kit-8 (CCK8) assay, flow cytometry, western blotting, and ELISA. Our data revealed that the exosomes were successfully isolated from rat BMSCs. The BMSC-exosomal miR-17-92 cluster improved neural functional recovery after SCI, as evidenced by an increased BBB score, improved pathological damage, reduced neuronal apoptosis, and decreased inflammatory factors release. Additionally, miR-17-92-exo treatment significantly inhibited lipopolysaccharide (LPS)-induced reduction in cell viability, increase in cell apoptosis, and upregulation of inflammatory factors in PC12 cells. The exosomal miR-17-92 cluster derived from BMSCs improved functional recovery and exhibited neuroprotective effects in SCI by alleviating apoptosis and inflammation.

Axonal endoplasmic reticulum tubules control local translation via P180/RRBP1-mediated ribosome interactions

Local mRNA translation in axons is critical for the spatiotemporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons; however, how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing rat hippocampal cultured neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER-ribosome interactions causes defects in axon morphology. Our results establish a role for the axonal ER in dynamically localizing mRNA translation, which is important for proper neuron 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.

Role of Cxcl12a on habenular axon projection in Danio rerio

The habenula is a forebrain region that is responsible for many emotional responses. The habenular axons project posteriorly to the interpeduncular nucleus (IPN), a region in midbrain. Correct projection of these habenular axons depend on chemokine signaling. Components of this signaling pathway include chemokine ligand, Cxcl12a, and chemokine receptor, Cxcr4b. Cxcr4b is made in the habenula, while Cxcl12a is made along the path of the habenular axons. Loss of either Cxcl12a or Cxcr4b results in abnormal anterior growth of habenular axons. However, the exact function of Cxcl12a as a directional cue at the habenula is not known. To explore this, overexpression of cxcl12a is being performed. Overexpression of cxcl12a is induced by heat shock in larvae carrying a transgenic line that produces GFP in the habenula and its axons. Heat shock is performed at 33 hours post fertilization (hpf), several hours prior to initial axon outgrowth. However, there have been challenges confirming overexpression of cxcl12a at this time point. Once overexpression is confirmed we will examine the habenular axons at 5 days post fertilization (dpf). We hypothesize that the overexpression of cxcl12a in larval zebrafish will cause a disruption in the growth of the axons of the habenula, implying that Cxcl12a is an attractant in habenular axon guidance. If no habenular axon disruption is noted, this implies that 33 hpf is not the correct window for chemokine signaling at the habenula or that excess Cxcl12a is insufficient in disrupting habenular axon pathfinding.

Transplantation of Neural Stem Cells Loaded in an IGF-1 Bioactive Supramolecular Nanofiber Hydrogel for the Effective Treatment of Spinal Cord Injury.

Spinal cord injury (SCI) leads to massive cell death, disruption, and demyelination of axons, resulting in permanent motor and sensory dysfunctions. Stem cell transplantation is a promising therapy for SCI. However, owing to the poor microenvironment that develops following SCI, the bioactivities of these grafted stem cells are limited. Cell implantation combined with biomaterial therapies is widely studied for the development of tissue engineering technology. Herein, an insulin-like growth factor-1 (IGF-1)-bioactive supramolecular nanofiber hydrogel (IGF-1 gel) is synthesized that can activate IGF-1 downstream signaling, prevent the apoptosis of neural stem cells (NSCs), improve their proliferation, and induce their differentiation into neurons and oligodendrocytes. Moreover, implantation of NSCs carried out with IGF-1 gels promotes neurite outgrowth and myelin sheath regeneration at lesion sites following SCI. In addition, IGF-1 gels can enrich extracellular vesicles (EVs) derived from NSCs or from nerve cells differentiated from these NSCs via miRNAs related to axonal regeneration and remyelination, even in an inflammatory environment. These EVs are taken up by autologous endogenous NSCs and regulate their differentiation. This study provides adequate evidence that combined treatment with NSCs and IGF-1 gels is a potential therapeutic strategy for treating SCI.

No evidence of fascicular injury following a low-volume intraneural injection of the median nerve: a cadaveric study

BackgroundThe test dose or hydrolocation technique allows rapid detection of spread location. Though its primary aim is to enhance safety in peripheral nerve blocks, evidence on the potential risks of...

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.

P38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions.

Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.

Altered brain connectivity, neuroinflammation and AD‐related markers following 7 days after repetitive mild traumatic brain injury in young wild‐type mice

AbstractBackgroundTraumatic brain injuries (TBI) substantially increase the risk for neurodegenerative disorders including tauopathies and synucleinopathies. Repetitive mild TBI (rmTBI) exacerbate damage in brain impacting cognitive and emotional processes through lifetime. Therefore, there is a critical need to identify the molecular mechanisms underlying TBI‐mediated brain dysfunction. In doing so, we can develop effective therapies as the etiology for dementia remain poorly understood. Our goal is to identify early, unbiased, and novel biomarkers of brain dysfunction following rmTBI. These include defects in the brain connectome and protein expression in the areas most functionally susceptible to damage following rmTBI.MethodTo do this, we exposed young male and female C57BL/6J wild‐type mice to two rmTBI (2 × 0.6 J impacts/24 h apart) using the closed head injury model of engineered rotational acceleration (CHIMERA) or sham procedures. We measured changes in brain functional connectivity (FC) using resting state functional MRI (rsfMRI) and graph theory, examined microstructural differences in white and grey matter regions through diffusion tensor imaging (DTI) analyses, surveyed neuropathological proteins using NanoString‐GeoMx Digital spatial protein profiling spatial profiling (DSP).ResultThe rsfMRI data revealed that rmTBI induces aberrant changes in the graph metrics such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in brain regions processing visual, auditory, and somatosensory information. The optic tract and thalamus were the most affected regions showing significant differences in phospho‐tau (S199), neuroinflammatory markers (GFAP, Iba‐1, GPNMB), and other proteolytic (cathepsin‐D) and proliferation (ki‐67) cell markers. We identified extensive white matter damage, defects in brain FC, and exacerbated anatomically distinct protein profiles.ConclusionThese findings align with results reported in individuals with TBI such as diffuse axonal damage, glial activation, and functional network disruption in the visual tract and specific thalamic regions. Upcoming studies will evaluate the potential use of using brain imaging along with molecular markers to predict longitudinal damage after rmTBI.

Computed tomography and magnetic resonance imaging of diffuse axonal injury in brain trauma in young children: retrospective study

INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of death and disability in children. Children’s TBI is associated with a number of characteristics that distinguish it from adults. Although the death rate associated with TBI has decreased over the past 2 decades, the disability of children who survived TBI continues to have a significant impact on the economy and public health of society as a whole.OBJECTIVE: To show the possibilities of computed tomography and magnetic resonance imaging in the diagnosis of traumatic diffuse axonal injuries in infants and young children.MATERIALS AND METHODS: In this work, we analyzed the CT and MRI data of 1334 children under 3 years of age with acute TBI who were treated at the Clinical and Research Institute of Emergency Pediatric Surgery and Trauma (730 boys, 604 girls). The age of the children was from 23 days to 3 years, the average age was 1 year 6 months. Computed tomography scans were performed on a 128-slice Ingenuity Elite scanner (Philips). Scanning of the area of interest (head + cervical spine) was carried out with the maximum possible reduction in indicators to minimize the radiation dose, including the iDose4 program. MRI was performed on a Phillips Achieva 3 T scanner with multiplanar T1- and T2WI, 2D and 3D isotropic images, FLAIR, SWI, DWI/DTI, and magnetic resonance angiography (MRA). No contrast enhancement was applied. Statistics: data processing was carried out using the GraphPad Prism 9 software package. The computing and graphic capabilities of the Excel spreadsheet editor were used. To compare the mean values of the data samples, ANOVA analysis of variance wasused; differences were considered significant at a significance level of p<0.05.RESULTS: 824 (61.8%) of 1334 children had a concussion, 510 (38.2%) had traumatic injuries of skull and brain from uncomplicated cephalohematomas and linear fractures to massive intracranial hematomas and total brain edema. Diffuse axonal injuries(DAI) type I and II on CT, further confirmed by MRI, were detected in 32 (6.27%) of all 510 children with TBI. 19 out of 32 hada combination with brain contusions, 13 with epi — and / or subdural hematomas of a small volume. MRI was performed in 89 out of 510 children under 3 years of age with intracranial injuries, in whom CT was initially performed. DAI of various types were detected by MRI in 92.13% (82/89) of the patients.DISCUSSION: DAI is one of the most common types of TBI, occurring in both mild and severe forms, and is a brain injury characterized by axonal disruption, resulting in lesions of white matter tracts over a wide area. Taking into account the fact that children with TBI were admitted to the institute with a significant spread (from 1 hour to 7 days), the initial CT scan was performed no later than one hour after admission and was supplemented by MRI. The criteria for CT and MRI prescribements after TBI were: clinical and neurological status at the time of admission. CT has low sensitivity for detecting DAI, as only large hemorrhagic (hyperdense) lesions of DAI are detected. The use of multiplanar reconstruction, as well as various options, such as 3D reconstruction, MIP and MinIP (maximum and minimum intensity projection) and others, allows for a detailed assessment of the brain parenchyma and increases the detection of DAI. In our study, DAI using MRI was detected in 92.13% of patients, and the most critical type of DAI III was detected in 100% of children with severe TBI with poor outcome and death of patients.CONCLUSION: Head CT is the preferred method for emergency radiology of TBI patients due to its affordability, speed of data acquisition, and ability to detect lesions requiring urgent neurosurgical intervention. In acute cases, MRI is chosen for patients with severe neurological impairment despite the absence of structural brain damage on CT. MRI is the method of choice for subacute and chronic TBI

Water-circulating probes significantly modify lesion length and axon damage in cooled radiofrequency ablations when compared with similar-sized standard radiofrequency probes in rats

IntroductionPreclinical research demonstrated water-cooled radiofrequency (CRF) ablations have a significant impact on structural and functional changes compared to standard radiofrequency (SRF) ablations. Clinical procedures utilizing RF to treat chronic pain...

A Swine Model of Changes in the Neuronal Electromagnetic Field After Traumatic Brain Injury: A Pilot Study.

Background Traumatic brain injury (TBI) is a global cause of disability and mortality. Treatment depends on mitigation of secondary injury resulting in axonal injury, necrosis, brain dysfunction, and disruption of electrical and chemical signaling in neural circuits. To better understand TBI, translational models are required to study physiology, diagnostics, and treatments in homologousspecies, such as swine. Electromagnetic fields (EMFs) from altered neural circuits can be measured and historically have been reliant on expensive shielding and supercooling in magnetoencephalography. Using proprietary induction sensors, it has been found that a non-invasive, non-contact approach with an engineered Mu-metal and copper mesh-shielded helmet effectively measures EMFs. This has not yet been investigated in swine models. We wished to evaluate the efficacy of this technology to assess TBI-dependent EMF changes in swine to describe the efficacy of these sensors and this model using a gravity-dependent controlled cortical impact (CCI). Methods A Yucatan miniswine was evaluated using non-contact, non-invasive proprietary induction sensors with an engineered dual-layer Mu-metal and interlaced copper mesh helmet with sensors within EMF channels connected to a helmet. Swine EMF recordings were obtained prior to induced gravity-dependent CCI followed by post-TBI measurements. Behavioral changesand changes in EMF measurements were assessed. EMF measurements were evaluated with an artificial intelligence (AI) model. Results Differences between room "noise" EMF measurements and pre-TBI swine electromagnetic field measurements were identified. Morphological characteristics between pre-injury and post-injury measurements were noted. AI modeling differentiated pre-injury and post-injury patterns in the swine EMF. Frequently identified frequencies seen post-injury were peaks at 2.5 Hz and 6.5 Hz and a valley at 11 Hz. The AI model identified less changes in the slope and thus decreased variation of EMF measurements post-TBI between 4.5 Hz and 7 Hz. Conclusions For the first time, it was identified thatcortical function in a swine can be appropriately measured using novel induction sensors and shielding isolated to a helmet and EMF channels. The swine model can be appropriately differentiated from the external noise signal with identifiably different pre-injury and post-injury EMFs. Patterns can be recognized within the post-injury EMF due to altered neural circuits that can be measured using these sensors continuously, non-invasively, and in real time.

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.

Sustained release of hydrogen sulfide from anisotropic ferrofluid hydrogel for the repair of spinal cord injury.

Spinal cord injury (SCI) results in massive neuronal death, axonal disruption, and cascading inflammatory response, which causes further damage to impaired neurons. The survived neurons with damaged function fail to form effective neuronal circuits. It is mainly caused by the neuroinflammatory microenvironment at injury sites and regenerated axons without guidance. To address this challenge, a ferrofluid hydrogel (FFH) was prepared with Ferric tetrasulfide (Fe3S4), carboxymethyl chitosan, and gold. Its internal structural particles can be oriented in a magnetic field to acquire anisotropy. Moreover, Fe3S4 can release hydrogen sulfide (H2S) with anti-inflammatory effects under acidic conditions. Regarding in vitro experiments, 0.01g/ml Fe3S4 FFH significantly reduced the inflammatory factors produced by LPS-induced BV2 cells. Oriented and longer axons of the induced neural stem cells loaded on anisotropic FFH were observed. In vivo experiments showed that FFH reduced the activated microglia/macrophage and the expression of pro-inflammatory factors in SCI rats through the NF-κB pathway. Moreover, it significantly promoted directional axonal regrowth and functional recovery after SCI. Given the critical role of inhibition of neuroinflammation and directional axonal growth, anisotropic Fe3S4 FFH is a promising alternative for the treatment of SCI.

132 A Novel Mechanism of Periventricular Strain Observed in Post-Mortem Human Brains for Mild Traumatic Brain Injury

INTRODUCTION: Mild traumatic brain injury (mTBI) can result in a myriad of long-term functional deficits reflecting diffuse axonal disruption. While microstructural anomalies in the periventricular regions of the brain have been identified through immunohistochemical analyses, diffusion tensor imaging and animal models, and contribute to a range of symptoms observed in mTBI, the mechanism of injury is not fully described. METHODS: Post-mortem human brains without space-occupying lesions and significant atrophy were included in this study. Using MRI and anatomical surface landmark localisation, cortical and subcortical markers were implanted along a sagittal plane in anterior, posterior and inferior periventricular regions as well as in the frontal, parietal, occipital and cerebellar lobes. A high-speed, high-resolution, two-dimensional imaging system was employed to measure brain displacement from direct low-velocity frontal impacts. Impact kinematics of the skull were measured using a DTS 6DX SLICE sensor array. Marker displacement in the anterior, inferior and posterior periventricular regions were calculated and individual frame position time-histories for markers' centre of gravity were recorded. RESULTS: Upon impact, the frontal horns of the lateral ventricles were observed to immediately collapse, followed by posterior fluid motion and occipital horn dilation not previously described in the literature. Substantial deformation was recorded in the periventricular areas, resulting in a significantly higher magnitude of strain relative to more superficial subcortical and cortical structures. In comparison, the posterior periventricular region of the brain recorded the highest magnitude of strain. CONCLUSIONS: This study describes the generation of unique high magnitude strain in the periventricular regions from ventricular fluid flow upon low-velocity frontal head impacts. While the clinical significance of the ventricular deformation remains to be elucidated, this represents an important association between the mechanism of injury and diffuse symptomatology observed in mTBI.

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.

Neuroprotective Effects of a Multi-Herbal Extract on Axonal and Synaptic Disruption in Vitro and Cognitive Impairment in Vivo.

Alzheimer's disease (AD) is a multifactorial disorder characterized by cognitive decline. Current available therapeutics for AD have limited clinical benefit. Therefore, preventive therapies for interrupting the development of AD are critically needed. Molecules targeting multifunction to interact with various pathlogical components have been considered to improve the therapeutic efficiency of AD. In particular, herbal medicines with multiplicity of actions produce cognitive benefits on AD. Bugu-M is a multi-herbal extract composed of Ganoderma lucidum (Antler form), Nelumbo nucifera Gaertn., Ziziphus jujuba Mill., and Dimocarpus longan, with the ability of its various components to confer resilience to cognitive deficits. To evaluate the potential of Bugu-M on amyloid-β (Aβ) toxicity and its in vitro mechanisms and on in vivo cognitive function. We illustrated the effect of Bugu-M on Aβ25-35-evoked toxicity as well as its possible mechanisms to diminish the pathogenesis of AD in rat cortical neurons. For cognitive function studies, 2-month-old female 3×Tg-AD mice were administered 400 mg/kg Bugu-M for 30 days. Behavioral tests were performed to assess the efficacy of Bugu-M on cognitive impairment. In primary cortical neuronal cultures, Bugu-M mitigated Aβ-evoked toxicity by reducing cytoskeletal aberrations and axonal disruption, restoring presynaptic and postsynaptic protein expression, suppressing mitochondrial damage and apoptotic signaling, and reserving neurogenic and neurotrophic factors. Importantly, 30-day administration of Bugu-M effectively prevented development of cognitive impairment in 3-month-old female 3×Tg-AD mice. Bugu-M might be beneficial in delaying the progression of AD, and thus warrants consideration for its preventive potential for AD.