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Report from Dr. Jerome Staal Masonic Centenary Medical Research Foundation Post Doctoral Fellow.

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

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.

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

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).

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,

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

USA

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

USA

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.

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

· National Neurotrauma Society (

USA

). Junior Post-Doctoral Research Presentation Award 2009

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.