Dr Dickson reports,

"In 2009/2010 we have continued to make steady progress in understanding the degenerative mechanisms underlying diffuse axonal injury using our in vitro models of acute axonal injury, as well as our in vivo model of localized brain injury. These models mimic important aspects of traumatic brain injury in cases of human head injury.

Specifically, Jerome Staal determined that acute axonal stretch injury induced an initial and progressive increase in calcium release from intracellular stores, which culminated in secondary axotomy and degeneration over the following 48 hours. Importantly, pharmacological inhibition of the calcium-activated phosphatase, clacineurin, significantly reduced secondary axotomy and increase reactive filopodial sprouting. Additionally, using an in vitro model of axonal shear injury, Catherine Blizzard demonstrated that mature cultured cortical neurons (pyramidal and interneurons) have an intrinsic potential to survive, extend new processes and re-establish appropriate neurite polarity.

Using our in vivo model of acute brain injury, Catherine Blizzard has shown that cortical excitatory (pyramidal) and inhibitory (inter-) neurons respond to injury in fundamentally different ways; unlike the previously characterized axonal sprouting response observed in cortical pyramidal neurons, a subpopulation of cortical interneurons respond to injury by remodeling their dendritic arbors.

Jyoti Chuckowree has recently returned to the laboratory following postdoctoral training in the techniques of implantation of cranial windows and chronic in vivo imaging of live anaesthetized mice. This combination of techniques was used to study neuronal plasticity in the ‘naïve’ brain and will now be married with our disease and injury models, enabling us to study injury and disease mechanisms in ‘real-time’ in living animals. Each of the above investigations resulted in peer-reviewed publications and conference presentations".

The results of this project is that four papers have been accepted and published in journals of international research significance, six abstracts have been presented to conferences both within Australia and overseas and a number of previously recorded honours bestowed on our researchers.

"This project is largely based on work from one of our PhD students Stan Mitew and our post-doctoral fellow Dr. Jerome Staal. In regard to Stan Mitews work, there have been significant advances in the understanding of how the extracellular amyloid-beta plaques, which are important features of Alzheimer’s disease, damage the surrounding neurons disrupting their structure and possibly their function. Using a transgenic line of mice that have specific mutations (PS1/APP) resulting in the formation of amyloid-beta plaques at 4-6 months of age, Stan illustrated a significant increase in the number of demyelinated nerve cells on the periphery and in close proximity plaques. Stan further supported this finding in Human cases of Alzheimer’s disease, which also showed increased levels of demyelination in regions of the brain with plaques. This work was presented at the Myelin Gordon Conference in California (2010) and has recently been published in the high-ranking Acta Neuropathologica. Supported by this work, we have recently proposed in a NHMRC project grant proposal to determine if the amyloid-beta induced demyelination of surround neurons is a primary or secondary event. Dr. Jerome Staal is currently using a cortical in vitro model to investigate this whilst also using a unique live in vivo imaging technique to validate the results. In support of this work Dr. Jerome Staal was awarded the Tasmanian Masonic Medical Research Fellowship and the Alzheimer’s Australia Post-doctoral Research Fellowship."

The results of this project is that two papers have been accepted and published in journals of international research significance, and an abstract has been presented to a conference in U.S.A . As before a number of honours have been bestowed on our researchers including a four year NHMRC Fellowship to Dr. Adele Woodhouse. Congratulations to all.

Brian Sims.

President. MCMRF.

2010

MCMRF – Focuses on the early brain alterations associated with Alzheimer’s disease.

 Progress Report 29/07 

CI and Research Fellow – Dr. Jerome Staal

Background

Alzheimer’s disease (AD) is the major cause of dementia in aged individuals, affecting approximately 11% of the population over 65 years and up to 50% of individuals over 85 years. The interval between initial diagnosis and death can vary considerably, usually 3-15 years, and with this decline comes an increasing dependence on primary carers and the health-care system. This significant social and economic burden is likely to increase over the next 10 years as Australia’s demographic profile changes. AD is the most intensely investigated nervous system disease within the neuroscience research community. Thus, tremendous advances have been achieved in our understanding of aspects of the AD process, such as the molecular genetics of familial AD and the protein composition of the principal characteristic lesions. The latter includes extracellular ß-amyloid (Aß) deposits and intracellular ‘neurofibrillary’ changes such as tangles, dystrophic neurites and neuropil threads. A major question remains as to the relationship between these pathological changes and the process by which specific subgroups of neurons slowly degenerate, leading to the gradual and progressive emergence of the clinical features of AD-related dementia. In this respect, Aß plaque formation appears to be an early pathological brain change. 

My underlying research hypothesis is that there is a specific pattern of damage to nerve cells associated with subsets of dense plaques that involves focal axon transport defects and cytoskeletal alteration . Subsequent aberrant regenerative sprouting in these damaged neurons leads to gradual degeneration and loss of connectivity that results in the progressive symptomology of the disease.

1. Critical early brain changes of Alzheimer’s disease

AD begins in the brain many years before clinical symptoms are overt. This ‘preclinical’ phase of the condition represents a form of ‘pathological aging’ of the brain where there are widespread Aß plaques typically associated with minor cognitive deficits that may represent incipient AD-type dementia. While it was widely believed that Aß deposits in these preclinical cases were relatively inert, we have determined that dystrophic neurites that are associated with these plaques are characterised by abnormal accumulations of neuronal cytoskeletal elements. I have also shown that the structure of these early and critical AD changes is similar to that seen following mechanical stretch injury to neurons. Thus, plaque-induced structural deformation of the brain may result in neuron constriction, leading to subsequent degenerative and regenerative changes that underlie dystrophic neurite formation.

To further investigate this, I am using advanced laser microscopy to image developing plaques in a transgenic AD mouse brain slice. I am focusing on the periphery of the new plaques to determine the early key neuronal changes that occur. Furthermore, we have recently determined that plaque-associated axonal changes characteristic of preclinical AD are morphologically and neurochemically identical to plaque-associated dystrophic neurites in our line of transgenic AD mice. Thus, the early/preclinical AD features in these mice may make for ideal models for exploring therapeutic strategies that ameliorate Aß and/or neuronal pathology long before it potentially develops into a more clinically significant pattern of neuronal degeneration that involves irreversible loss of connectivity.

I am involved in a grant submitted on this work to the National Health and Medical research Council (NHMRC).

One of the first consequences of plaque-induced neuronal damage is alterations in cell signaling. Calcium is an important regulator of cell signaling as well as cell death. Very recent studies have proposed that there is increased calcium signaling in nerve cells around AD plaques and that these ‘hyperactive’ neurons propagate these pathological signals to neurons away from the plaque. Interestingly, I have found a similar response when I constrict and stretch nerve cells grown in culture (an injury we propose plaques may induce to surrounding nerve cells). I have found that this disruption in neuron calcium signalling activates various pathways including aberrant regenerative sprouting and eventually cell death. Currently, I am investigating the mechanisms involved in the activation of these pathways and develop methods of inhibiting them. I have formed collaborations with Dr. Lisa Foa at the University of Tasmania. Dr. Foa has experience in calcium imaging techniques in cultured nerve cells.

The results of this work are about to be submitted to the prestigious Journal of Neuroscience

2. Therapeutic interventions 

There is increasing evidence that therapeutics used for brain trauma patients may also be beneficial in the treatment of AD. This is likely, as there are many shared pathological features between brain trauma and AD, such as axonal swellings. I have recently found that an anti-cancer drug, Taxol, is particularly beneficial in preventing neuronal death following injury of neurons in culture. Unfortunately, this drug does not cross the blood brain barrier unless there is significant damage to the brain. Recently, I formed collaboration with a research group at the School of Chemistry (University of Tasmania) headed by Dr Jason Smith. Dr Smith has considerable experience in the chemical synthesis of organic structures and is currently working with a compound, called Baccatin III, used as a precursor to Taxol. He will chemically alter this compound to synthetically produce a number of new drugs. We aim to develop a new drug that has a greater therapeutic action compared to Taxol, and are also capable of crossing the blood brain barrier. So far, we have two new drugs, which I am currently testing using our in vitro injury models. Positive candidates will then be tested in our animal models of injury and AD.

I have submitted a grant on this work to the University of Tasmania Internal Reviewed Grant System (IRGS).

3. Grant applications

This year I have submitted grants to the following funding agencies:

·         National Health and Medical Research Council ($360 000)

·         University of Tasmania (IRGS) ($18 650)

·         Australia Alzheimer’s Association ($45 000)

·         Australian Brain Foundation ($25 000)

·         The Marian and EH Flack Foundation ($14 450)

4. Conference Presentations 

Presentations at conferences (these include conferences to be attended in the coming two months):

·         Cambridge Brain Repair Council Summer Symposium. March 3-8, 2009. Cambridge University, UK.

·         International Neurotrauma Symposium. September 7-12, 2009. San Diego, USA.

·         Society for Neuroscience Annual Meeting. October 17-21. Chicago, USA.

 5. Publications for the year 2009: 

Staal JA, Dickson TC, Chung RS, Vickers JC. Disruption of the ubiquitin proteasome system following axonal stretch injury accelerates progression to secondary axotomy. J Neurotrauma. 2009 May;26(5):781-8. 

Staal JA, Dickson TC, Gasperini R, Liu Y, Foa L,, Vickers JC. Initial calcium release from intracellular stores followed by calcium mismetabolism is linked to secondary axotomy following transient axonal stretch injury. J Neuroscience Submission 2009, Aug 1.

 6. Awards for the year 2009 

·         Southern Cross Tasmania Young Achiever of The Year Award 2009 Finalist.

·         National Neurotrauma Society (USA). Junior Post-Doctoral Research Presentation Award 2009

7. Supervision of students 

I am currently involved in the supervision of two PhD students: Yao Liu and Stan Mitew. Yao Liu is principally working on the calcium aberrations that are associated with neuronal injury and AD. Stan Mitew is working with me on the Laser imaging of AD plaque formation in the transgenic AD mice models.  

Dr Jerome Staal is the Masonic Centenary Medical Research Foundation Post Doctoral Fellow. He recently submitted a progress report to the Foundation, a précis of  which was part of a to Grand Lodge Communications in August 2009.

Masonic Centenary Medical Research Foundation

Catherine Blizzard PhD. student

I am pleased to report on the progress of Catherine Blizzard, our very own PhD student.

The Foundation is proud of her achievements and conveys to her best wishes for the many successful years in the future which I am sure lies ahead of her.

She writes,

“I am currently in the final stages of writing up my thesis and I am planning on submitting it in late July and hopefully have the thesis accepted by the end of the year. I am more than happy for you to publish a report in regards to my doctorate, and additionally I would be happy to give a talk at the next annual meeting about the main findings from my thesis. After I have finished my thesis I am planning on applying for an Australian fellowship for two years to continue my studies in Tasmania with James Vickers, Tracey Dickson and Anna King.  If I am successful after this fellowship I ideally plan to continue my work in an international lab, with the end goal to return to Tasmania and the NeuroRepair group. I would like to thank Tasmanian Masonic Centenary Research Foundation for their support of my thesis and I hope we can stay in touch long after I have graduated and throughout my career.”

Below is her final report to the Foundation:

 “Neuronal regeneration and plasticity in response to focal brain injury

Despite the previous dogma that the adult brain cannot recover following injury, recent research is indicating that the brain does have a remarkable capacity for repair and remodeling following injury.  Acquired brain injury affects about one in 45 Australians. The consequences of brain injury remain severe, as there are still no effective treatments.

My PhD studies investigated the capacity for regeneration and plasticity following injury, in a range of in vitro and in vivo models of neural injury.  I demonstrated the injured neurons can respond actively to injury.  My studies demonstrate a novel neuronal response to traumatic brain, my data suggesting that the cerebral cortex [the brain's outer layer of grey matter surrounding the cerebrum] is capable of significant remodelling following injury, specific to neuronal type.  There are main two types of neurons in the cortex – pyramidal neurons and interneurons.  I looked at both types and found that pyramidal neurons attempt axonal regeneration into the injury site, whereas interneurons reorganised their processes away from the injury site to undamaged areas of the cortex. I investigated this pyramidal regenerative response in vitro and determined that it may not actually be a good response of the neurons and would most likely not lead to repair. However, my studies demonstrate that the other type of neurons in the adult brain, the interneurons have an unappreciated capacity for remodelling away from the actual injury, and that these neurons are attempting to rewire the brain following an injury.  These studies describe how natural brain remodelling and healing may improve an outcome after acquired forms of brain injury and represent a new therapeutic window following brain injury, giving sufferers of acquired brain injury and neurodegenerative disease alike, new hope.

“The funding I received from the Masonic Centenary Medical Research Foundation

has successfully supported my studies on a laboratory basis.  The grant has also enabled me to attend an international Society of Neuroscience conference where I presented my work in 2008.  Attendance to this conference was an invaluable experience for my academic development as well as forming international collaborations.  Additionally this funding supported a trip to Cambridge in March 2010, to attend a neuroscience school. While in Cambridge I met with many experts in my fields and established international collaborations.  This will allow me to apply for national funding and ideally set up an international post doc.  The funding provided has therefore enabled me to potentially become competitive on an international scale.”

Appended to the report is a list of twenty one (21) of her joint publications and conference abstracts. The most recent, as the first nominated researcher, published May 28^th and accepted into a prestigious journal is entitled,

“Focal Damage to the Adult Rat Neocortex Induces Wound Healing Accompanied by Axonal Sprouting and Dendritic Structural Plasticity”.

It is gratifying to note that co-authors of this paper included three (3) other researchers associated with our Foundation, namely Dr Anna E. King, Prof James C. Vickers and Dr Tracey C. Dickson.

Be proud of the contribution that the ‘Foundation’ has had on world class research in this

little island and may we continue to fight above our weight.

Brian Sims

President

August  2010

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