Tracey C Dickson

University of Tasmania, Hobart Town, Tasmania, Australia

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Publications (58)281.1 Total impact

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    ABSTRACT: A new model for studying localised axonal stretch injury is presented, using a microfluidic device to selectively culture axons on a thin, flexible poly (dimethylsiloxane) membrane which can be deflected upward to stretch the axons. A very mild (0.5% strain) or mild stretch injury (5% strain) was applied to primary cortical neurons after 7 days growth in vitro. The extent of distal degeneration was quantified using the degenerative index (DI, the ratio of fragmented axon area to total axon area) of axons fixed at 24 h and 72 h post injury (PI), and immunolabelled for the axon specific, microtubule associated protein-tau. At 24 h PI following very mild injuries (0.5%), the majority of the axons remained intact and healthy with no significant difference in DI when compared to the control, but at 72 h PI, the DI increased significantly (DI = 0.11 ± 0.03). Remarkably, dendritic beading in the somal compartment was observed at 24 h PI, indicative of dying back degeneration. When the injury level was increased (5% stretch, mild injury), microtubule fragmentation along the injured axons was observed, with a significant increase in DI at 24 h PI (DI = 0.17 ± 0.02) and 72 h PI (DI = 0.18 ± 0.01), relative to uninjured axons. The responses observed for both mild and very mild injuries are similar to those observed in the in vivo models of traumatic brain injury, suggesting that this model can be used to study neuronal trauma and will provide new insights into the cellular and molecular alterations characterizing the neuronal response to discrete axonal injury.
    Biomicrofluidics 07/2014; 8:044110. · 3.39 Impact Factor
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    ABSTRACT: Using a novel metabolomics approach the current study aimed to further characterize the functional attributes of alpha-synuclein that mediate its involvement in neurodegeneration. The metabolic profiles of alpha-synuclein knockout and A53T mutant overexpressing mouse brains were studied using proton nuclear magnetic resonance (1H NMR) and liquid chromatography mass spectrometry (LC/MS). Gene deletion and mutation were both associated with significant alterations in brain energy metabolism when compared with their respective wild-type controls. These changes indicated deficiencies in key metabolic pathways, including the tricarboxylic acid cycle, and significant differences in the concentrations of small molecules including adenine nucleotides, taurine, NAD+ and glutamine. Analysis of the metabolic pathways affected by both knockout and mutation further indicated involvement of alpha-synuclein in metabolic pathways of energy metabolism, cellular redox status and glycerophospholipid metabolism. As such, our data identify novel functions of alpha-synuclein, validate previous reports describing its contribution to energy metabolism and lipid synthesis and support the use of metabolomic analysis as a fundamental technique in defining the effect of protein expression and mutation in genetic models.
    Metabolomics 02/2014; 10(1). · 4.43 Impact Factor
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    ABSTRACT: Introduction: Multiple system atrophy (MSA) closely resembles Parkinson’s disease (PD) clinically, but with a range of autonomic signs. However, unlike PD that displays primarily neuronal pathology, MSA exhibits widespread astrogliosis and the occurrence of α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. To investigate the relationship between α-syn inclusions and neuroinflammation in MSA, we conducted quantitative morphometric analysis on MSA cases, and cell culture and animal model studies. Methods: Using Imaris software, we obtained “skinned” three-dimensional models of GFAP-positive astrocytes in MSA and normal tissue (n = 75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to GCI. Results: Astrocyte activation results in highly ramified astrocyte morphology with extended and thickened processes. Astrocytes proximal to GCI-containing oligodendrocytes (r < 25 µm) had significantly (p, 0.05) longer and thicker processes than distal astrocytes (r > 25 µm), with a reciprocal linear correlation (m, 90 µm2) between mean process length and radial distance to the nearest GCI (R2, 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Activated astrocytes were also observed in close proximity to α-syn deposits in a unilateral rotenone-lesion mouse model. Moreover, unilateral injection of MSA tissue-derived α-syn into the mouse medial forebrain bundle resulted in widespread neuroinflammation in the α-syn-injected, but not sham-injected hemisphere. Conclusion: Taken together, our data suggests that localized extracellular concentrations of α-syn may underlie both astrocyte and oligodendrocyte MSA pathological features.
    2013 Gold Coast Health and Medical Research Conference Program; 11/2013
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    ABSTRACT: With the introduction of hobby laser engravers/cutters, the use of CO2 laser micromachining on poly (methyl methacrylate) (PMMA) has the potential for flexible, low cost rapid prototyping of microfluidic devices. Unfortunately, the feature size created by most entry-level CO2 laser micromachining systems is too large to become a functional tool in analytical microfluidics. In this paper, we report a novel method to reduce the feature size of microchannels and the bulges formed at the rim of channel during CO2 laser micromachining by passing the laser beam through a stainless steel pinhole. Without the pinhole, the channel width was typically 300 µm wide. However, when 50 µm or 35 µm diameter pinholes were used, channel widths of 60 µm and 25 µm, respectively, could be obtained. The height of the bulge deposited directly next to the channel was reduced to less than 0.8 µm with the pinhole during ablation. Separations of fluorescent dyes on devices ablated with and without the pinhole were compared. On devices fabricated with the pinhole, the number of theoretical plates/m was 2.2 fold higher compared to devices fabricated without the pinhole, and efficiencies comparable to embossed PMMA and laser ablated glass chips were obtained. A mass-produced commercial hobby laser (retailing at ~$2,500), when equipped with a $500 pinhole, represents a rapid and low-cost approach to the rapid fabrication of rigid plastic microchips including the narrow microchannels required for microchip electrophoresis.
    Analytical Chemistry 09/2013; · 5.70 Impact Factor
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    ABSTRACT: Neurofilaments have been proposed to have a significant role in attempted axonal regeneration following a variety of forms of injury. The neurofilament triplet proteins of the central nervous system are comprised of light (NF-L), medium (NF-M) and heavy (NF-H) chains and are part of the type IV intermediate filament family (IF). We sought to define the role of NF-L in the neuronal response to trauma and regeneration by examining the effect of total absence of the NF-L protein on neuronal maturation and response to axotomy. This study utilised an in vitro model comprising relatively mature cortical murine neurons derived from either wild-type embryonic (E15) mice or mice with a genetic knockout of NF-L (NF-L KO). Whilst NF-L KO neurons developed to relative maturity at a comparable rate to wild-type control neurons, NF-L KO neurons demonstrated relatively increased expression of α-internexin and decreased expression of NF-M. Furthermore, we demonstrate that α-internexin co-immunoprecipitates with the neurofilament binding protein NDel1 in NFL-KO cortical neurons in vitro. Following localised axotomy, NF-L KO neurons demonstrated reduced APP accumulation in damaged neurites as well as a significant reduction in the number of axons regenerating (4.79+/-0.58 sprouts) in comparison to control preparations (10.47+/-1.11 sprouts) (p<0.05). These studies indicate that neurofilaments comprising NF-L have a dynamic role in the reactive and regenerative changes in axons following injury.
    Journal of neurotrauma 06/2013; · 4.25 Impact Factor
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    ABSTRACT: Background and Objective: Multiple system atrophy (MSA) closely resembles Parkinson’s disease clinically, but with a range of autonomic signs, resulting in its designation as a Parkinson’s-plus disease. However, unlike Parkinson’s disease that displays primarily neuronal pathology, MSA exhibits widespread astrogliosis and the occurrence of (a-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. To investigate the relationship between a-syn inclusions and astrogiosis in MSA, we conducted quantitative morphometric analysis on MSA cases, and cell culture and animal model studies. Methods: Using Imaris software, we obtained “skinned” three-dimensional models of GFAP-positive astrocytes in MSA tissue (n = 35) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to GCI. Results: Astrocyte activation results in highly ramified astrocyte morphology with extended and thickened processes. Astrocytes proximal to GCI-containing oligodendrocytes (r < 7 microns) had significantly (p, 0.05) longer and thicker processes than distal astrocytes (r > 20 microns), with an inverse linear correlation (m, 92 microns squared ) between mean process length and radial distance to the nearest GCI (R2 , 0.71). In primary cell culture studies, a-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear a-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Moreover, unilateral injection of MSA tissue-derived a-syn into the mouse medial forebrain bundle resulted in widespread astrogliosis in the a-syn-injected, but not sham-injected hemisphere. Conclusions: Taken together, our data suggests that localized extracellular concentration gradients of a-syn may underlie both astrocyte and oligodendrocyte MSA pathological features.
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    ABSTRACT: Modelling the complex process of neuromuscular signalling is key to understanding not only normal circuit function but also importantly the mechanisms underpinning a range of degenerative diseases. We describe a novel in vitro model of the lower motor neuron-neuromuscular junction circuit, incorporating primary spinal motor neurons, supporting glia and skeletal muscle. This culture model is designed to spatially mimic the unique anatomical and cellular interactions of this circuit in compartmented microfluidic devices, such that the glial cells are located with motor neuron cell bodies in the cell body chamber and motor neuron axons extend to a distal chamber containing skeletal muscle cells whilst simultaneously allowing targeted intervention. This model is suitable for use in conjunction with a range of downstream experimental approaches and could also be modified to utilise other cellular sources including appropriate immortal cell lines, cells derived from transgenic models of disease and also patient derived stem cells.
    Journal of neuroscience methods 06/2013; · 2.30 Impact Factor
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    ABSTRACT: Amyloid-β (Aβ) plaque accumulation in Alzheimer's disease (AD) is associated with glutamatergic synapse loss, but less is known about its effect on inhibitory synapses. Here, we demonstrate that vesicular γ-aminobutyric acid (GABA) transporter (VGAT) presynaptic bouton density is unaffected in human preclinical and end-stage AD and in APP/PS1 transgenic (TG) mice. Conversely, excitatory vesicular glutamate transporter 1 (VGlut1) boutons are significantly reduced in end-stage AD cases and less reduced in preclinical AD cases and TGs. Aged TGs also show reduced protein levels of VGlut1 and synaptophysin but not VGAT or glutamate decarboxylase (GAD). These findings indicate that GABAergic synapses are preserved in human AD and mouse TGs. Synaptosomes isolated from plaque-rich TG cortex had significantly higher GAD activity than those from plaque-free cerebellum or the cortex of wild-type littermates. Using tissue fractionation, this increased activity was localized to glial synaptosomes, suggesting that Aβ plaques stimulate increased astrocyte GABA synthesis.
    Neurobiology of aging 04/2013; · 5.94 Impact Factor
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    ABSTRACT: Amyloid-β plaque accumulation in Alzheimer's disease (AD) is associated with dystrophic neurite (DN) formation and synapse loss in principal neurons, but interneuron pathology is less clearly characterized. We compared the responses of neuronal processes immunoreactive for either neurofilament triplet (NF(+)) or calretinin (CR(+)) to fibrillar amyloid (Aβ) plaques in human end-stage and preclinical AD, as well as in APP/PS1 and Tg2576 transgenic mouse AD models. Neurites traversing the Aβ plaque core, edge, or periphery, defined as 50, 100, and 150% of the plaque diameter, respectively, in human AD and transgenic mouse tissue were compared to age-matched human and wild-type mouse controls. The proportion of NF(+) neurites exhibiting dystrophic morphology (DN) was significantly larger than the proportion of dystrophic CR(+) neurites in both human AD and transgenic mice (p < 0.01). Additionally, the number of NF(+), but not CR(+), DNs, correlated with Aβ plaque size. We conclude that CR(+) interneurons appear to be more resistant than NF(+) neurons to AD-mediated cytoskeletal pathology.
    Frontiers in Neuroanatomy 01/2013; 7:30. · 4.06 Impact Factor
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    ABSTRACT: The neurofilament light (NFL) subunit is considered as an obligate subunit polymer for neuronal intermediate filaments comprised of the neurofilament (NF) triplet proteins. We examined cytoskeletal protein levels in the cerebral cortex of NFL knockout (KO) mice at postnatal day 4 (P4), 5 months and 12 months (5m, 12m) of age, compared with age-matched wild-type (WT) mice of a similar genetic background (C57BL/6). The absence of NFL protein resulted in a significant reduction of phosphorylated and dephosphorylated NFs (NF-P, NF-DP), the medium NF subunit (NFM) and the intermediate filament α-internexin (INT) at P4. At 5 months, NF-DP, NFM and INT remained significantly lower in knockouts. At 12 months, NF-P was again significantly decreased, and INT significantly increased, in knockouts compared to wildtype. In addition, protein levels of class III neuron-specific beta-tubulin and microtubule-associated protein 2 (MAP2) were significantly increased in NFL KO mice at P4, 5 months and 12 months, whereas beta-actin levels were significantly decreased at P4. Immunocytochemical studies demonstrated that NF-DP accumulated abnormally in the perikarya of cortical neurons by 5 months of age in NFL KO mice. Neurons that lacked NF triplet proteins, such as calretinin-immunolabeled non-pyramidal cells, showed no alterations in density or cytoarchitectural distribution in NFL KO mice at 5 months relative to WT mice, although calretinin protein levels were decreased significantly after 12 months in NFL KO mice. These findings suggest that a lack of NFL protein alters the expression of cytoskeletal proteins and disrupts other NF subunits, causing intracellular aggregation but not gross structural changes in cortical neurons or cytoarchitecture. The data also indicate that changes in expression of other cytoskeletal proteins may compensate for decreased NFs. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 11/2012; · 3.66 Impact Factor
  • Ruth E J Musgrove, Anna E King, Tracey C Dickson
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    ABSTRACT: α-Synuclein is a pre-synaptic chaperone and its accumulation contributes to differential cell loss in Parkinson's disease. Cytoplasmic expression of α-synuclein can directly modulate apoptotic pathways and contribute to cell survival, whereas induced over-expression of the protein causes oxidative stress through mitochondrial and cytosolic free-radical production. This study aimed to clarify the contribution of endogenous α-synuclein to oxidative stress and its association with cell death. Primary cortical neurons were derived from α-synuclein knock-out (Snca-/-) and wild-type (C57BL/6; WT) mice and treated with in vitro models of oxidative-stress, complex I inhibition and excitotoxicity. Mitochondrial free radical production was determined in isolated mitochondria derived from each mouse strain. Snca-/- derived cortical cultures were more susceptible (P < 0.05) to oxidative-stress, but not excitotoxicity. This result was determined by significant increases in cell death (Propidium-Iodide staining) after 6 h treatment in Snca-/- (45 % ± 2.7 SEM), relative to WT (33 % ± 3.9 SEM) cultures. α-Synuclein also confers significant (P < 0.05) resistance to low-dose (5 nM) rotenone toxicity, with a twofold reduction in cell death in WT, compared with Snca-/- cortical neurons. The expression of α-synuclein had no effect on cortical glutathione levels, or the production of reactive oxygen intermediates in isolated mitochondria. These data indicate that endogenous levels of α-synuclein confer resistance to oxidative stress downstream of free radical production and scavenging. The current data suggest that α-synuclein prevents cytochrome c release and apoptosis through inhibition of the MAPK signalling pathway.
    Neurotoxicity Research 08/2012; · 2.87 Impact Factor
  • Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2012; 8(4 (Suppl. 2)):P147. · 14.48 Impact Factor
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    ABSTRACT: Axonal degeneration is a prominent feature of amyotrophic lateral sclerosis (ALS) both in lower motor nerves as well as descending white matter axons in the spinal cord of human patients. Although the pathology of lower motor axonal degeneration has been described in both human ALS and related transgenic animal models, few studies have examined the pathological features of descending axon degeneration, particularly in mouse models of ALS. We have examined the degeneration of white matter tracts in the G93A mutant superoxide dismutase-1 (mSOD1+) mouse spinal cord white matter from 12 weeks of age to end-stage disease. In a G93A mSOD1 mouse model where green fluorescent protein was expressed in neurons (mSOD1+/GFP+), degeneration of white matter tracts was present from the ventral to dorsolateral funiculi. This pattern of axonal pathology occurred from 16 weeks of age. However, the dorsal funiculus, the site of the major corticospinal tract in mice, showed relatively less degeneration. Immunohistochemical analysis demonstrated that the neurofilament light chain (NFL) and neuronal intermediate filament protein alpha-internexin accumulated in axon swellings in the spinal white matter. Increased levels of alpha-internexin protein, in mSOD1+ mouse spinal cord tissue, were demonstrated by Western blotting. In contrast, degenerating axons did not show obvious accumulations of neurofilament medium and heavy chain proteins (NFM and NFH). These data suggest that white matter degeneration in this mouse model of ALS is widespread and involves a specific molecular signature, particularly the accumulation of NFL and alpha-internexin proteins.
    Brain research 05/2012; 1465:90-100. · 2.46 Impact Factor
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    ABSTRACT: Glutamate excitotoxicity is a major pathogenic process implicated in many neurodegenerative conditions, including AD (Alzheimer's disease) and following traumatic brain injury. Occurring predominantly from over-stimulation of ionotropic glutamate receptors located along dendrites, excitotoxic axonal degeneration may also occur in white matter tracts. Recent identification of axonal glutamate receptor subunits within axonal nanocomplexes raises the possibility of direct excitotoxic effects on axons. Individual neuronal responses to excitotoxicity are highly dependent on the complement of glutamate receptors expressed by the cell, and the localization of the functional receptors. To enable isolation of distal axons and targeted excitotoxicity, murine cortical neuron cultures were prepared in compartmented microfluidic devices, such that distal axons were isolated from neuronal cell bodies. Within the compartmented culture system, cortical neurons developed to relative maturity at 11 DIV (days in vitro) as demonstrated by the formation of dendritic spines and clustering of the presynaptic protein synaptophysin. The isolated distal axons retained growth cone structures in the absence of synaptic targets, and expressed glutamate receptor subunits. Glutamate treatment (100 μM) to the cell body chamber resulted in widespread degeneration within this chamber and degeneration of distal axons in the other chamber. Glutamate application to the distal axon chamber triggered a lesser degree of axonal degeneration without degenerative changes in the untreated somal chamber. These data indicate that in addition to current mechanisms of indirect axonal excitotoxicity, the distal axon may be a primary target for excitotoxicity in neurodegenerative conditions.
    ASN Neuro 01/2012; 4(1). · 3.64 Impact Factor
  • R E J Musgrove, A E King, T C Dickson
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    ABSTRACT: α-Synuclein is the major protein component of Lewy bodies--the pathological hallmark of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Its accumulation into intracellular aggregates is implicated in the process of Lewy body formation. However, its roles in both normal function, and disease, remain controversial. Using a novel model of chronic oxidative stress in cultured dopaminergic and cortical neurons, we report that endogenous α-synuclein is upregulated in response to low dose toxicity. This response is conserved between subpopulations of cortical and dopaminergic neurons, and confers relative resistance to apoptosis following secondary insult. Additional acute oxidative stress leads to intracellular accumulation of α-synuclein. These punctate deposits colocalize with ubiquitin, which is central to proteosome-mediated protein degeneration, and is the second major component of Lewy bodies. The current results imply that differential levels of α-synuclein expression may influence neuronal vulnerability in chronic neurodegenerative diseases. They further support a 'two hit' hypothesis for Lewy body formation, whereby mild stress causes a protective upregulation of α-synuclein. However, such increased levels of α-synuclein may drive its accumulation, following additional toxic insult. Finally, these results support a common mechanism for degeneration of dopaminergic and cortical neurons, affected in PD, and DLB, respectively.
    Neurotoxicity Research 05/2011; 19(4):592-602. · 2.87 Impact Factor
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    ABSTRACT: Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adaptive cellular responses and may retain a capacity for structural plasticity. We have investigated the cellular and architectural alterations following focal experimental brain injury, as well as the specific capacity for structural remodeling of neuronal processes in a subset of cortical interneurons. Focal acute injury was induced by transient insertion of a needle into the neocortex of anesthetized adult male Hooded-Wistar rats and thy1 green fluorescent protein (GFP) mice. Immunohistochemical, electron microscopy, and bromodeoxyuridine cell proliferation studies demonstrated an active and evolving response of the brain to injury, indicating astrocytic but not neuronal proliferation. Immunolabeling for the neuron-specific markers phosphorylated neurofilaments, α-internexin and calretinin at 7 days post injury (DPI) indicated phosphorylated neurofilaments and α-internexin but not calretinin immunopositive axonal sprouts within the injury site. However, quantitative studies indicated a significant realignment of horizontally projecting dendrites of calretinin-labeled interneurons at 14 DPI. This remodeling was specific to calretinin immunopositive interneurons and did not occur in a subpopulation of pyramidal neurons expressing GFP in the injured mouse cortex. These data show that subclasses of cortical interneurons are capable of adaptive structural remodeling.
    Cerebral Cortex 02/2011; 21(2):281-91. · 8.31 Impact Factor
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    ABSTRACT: Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9-10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson's disease. Metallothioneins (MTs) are a class of low-molecular weight (6-7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments.
    Neurotoxicity Research 01/2011; 19(1):115-22. · 2.87 Impact Factor
  • Alzheimer's and Dementia 07/2010; 6:S385. · 14.48 Impact Factor
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    ABSTRACT: We have investigated alterations in myelin associated with Abeta plaques, a major pathological hallmark of Alzheimer's disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Abeta pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Abeta plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Abeta plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.
    Acta Neuropathologica 03/2010; 119(5):567-77. · 9.73 Impact Factor
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    ABSTRACT: Acute axonal shear and stretch in the brain induces an evolving form of axonopathy and is a major cause of ongoing motor, cognitive and emotional dysfunction. We have utilized an in vitro model of mild axon bundle stretch injury, in cultured primary cortical neurons, to determine potential early critical cellular alterations leading to secondary axonal degeneration. We determined that transient axonal stretch injury induced an initial acute increase in intracellular calcium, principally derived from intracellular stores, which was followed by a delayed increase in calcium over 48 h post-injury (PI). This progressive and persistent increase in intracellular calcium was also associated with increased frequency of spontaneous calcium fluxes as well as cytoskeletal abnormalities. Additionally, at 48 h post-injury, stretch-injured axon bundles demonstrated filopodia-like sprout formation that preceded secondary axotomy and degeneration. Pharmacological inhibition of the calcium-activated phosphatase, calcineurin, resulted in reduced secondary axotomy (p < 0.05) and increased filopodial sprout length. In summary, these results demonstrate that stretch injury of axons induced an initial substantial release of calcium from intracellular stores with elevated intracellular calcium persisting over 2 days. These long-lasting calcium alterations may provide new insight into the earliest neuronal abnormalities that follow traumatic brain injury as well as the key cellular changes that lead to the development of diffuse axonal injury and secondary degeneration.
    Journal of Neurochemistry 12/2009; 112(5):1147-55. · 3.97 Impact Factor

Publication Stats

1k Citations
281.10 Total Impact Points


  • 1997–2014
    • University of Tasmania
      • • Wicking Dementia Research and Education Centre
      • • School of Medicine
      • • Menzies Research Institute
      • • Rural Clinical School (RCS)
      Hobart Town, Tasmania, Australia
  • 2007–2011
    • Menzies Research Institute
      Hobart Town, Tasmania, Australia
  • 2002
    • University of Newcastle
      • Department of Biological Sciences
      Newcastle, New South Wales, Australia
    • Mount Sinai School of Medicine
      • Department of Neuroscience
      Manhattan, New York, United States