Principal Focus: Alzheimer's disease and other neurodegenerative illnesses including Parkinson's disease, motor neurone disease, Huntington's disease, dementia with Lewy Bodies and more.

Directed by ARC Federation Fellow Professor Ashley Bush, the Oxidation Disorders Laboratory (ODL) examines four major themes:

• Oxidative stress in neurological disorders;
• The molecular and cellular basis of neurotoxicity associated with the deposition of aggregating proteins in neurodegenerative disorders;
• Understanding the interactions between cellular proteins and biologically important metals;
• Developing new therapeutic approaches based on insights gained through this basic research.

Researchers believe that the hallmark proteins associated with AD - the Amyloid Precursor Protein (APP) and its cleavage product amyloid beta (A-beta) - are components of the system that regulates the import and export of the vital trace metals - copper, zinc and iron - within the brain. Even a subtle imbalance in the normally tight regulation of metals can permit these proteins to interact abnormally and generate destructive free radicals by redox chemistry.

Treating Alzheimer’s disease

The laboratory is working to:

• Advance our understanding of the mechanism of action of transition
  metal ionophores: a novel class of compound that includes PBT2, a drug currently undergoing clinical trials for Alzheimer's disease.
• Identify blood based biomarkers to diagnose Alzheimer's disease.
• Understand the way that drugs can restructure the brain to compensate for disease pathology.
• Understand the role of APP in maintaining copper homeostasis in the brain.
• Characterise the role of APP in maintaining copper homeostasis in the brain.
• Investigate the role of tau (a microtubule stabilising protein also implicated in Alzheimer's disease) in the transport of metals.
• Understand the biochemical link between cholesterol, neuronal metal balance and Alzheimer's disease, as the lipid components of brain cells (especially cholesterol) influence the way in which known AD related proteins are processed.

Achievements

PBT and its class of drugs benefited cognition in animal models for AD and manifested in significant changes in neuronal biochemistry and structure. These changes reflect what appears to be a restorative, disease-modifying
effect which is in clear contrast to the short-term stimulatory effects provided by current treatments for AD.

Robert Cherny co-authored a paper published in the high impact neuroscience journal ‘Neuron’; describing for the first time a novel
neuroprotective compound for AD. The compound was developed in the Oxidation Biology Laboratory in collaboration with Melbourne pharmaceutical company, Prana Biotechnology.

Publication of the Neuron paper coincided with our report in Lancet Neurology on the efficacy of the drug PBT2 in a Phase IIa trial in a cohort of AD patients. Cognitive benefits demonstrated over only 12 weeks of treatment both validated the hypothesis behind our drug development program and is a massive step towards slowing, and perhaps eventually halting, the disease.

This new drug is also useful as a tool for studying the age-related changes to brain biochemistry that underlie common age-related cognitive impairment and which are exaggerated and accelerated in AD.

Michael Cater's research on how intracellular copper deficiency
increases Aβ secretion was recently published in the Biochemical Journal.

James Duce has proposed a novel function for APP as a regulator of intracellular iron homeostasis. Progress on this work was presented
at the International Alzheimer’s and Parkinson’s Disease Conference in Prague in 2009. These monumental findings on the role of APP as an iron export ferroxidase are currently being reviewed for publication in the prestigious Nature journal.

Ya Hui Hung's recent publication in the Journal of Biological Chemistry showed how the binding of copper to Aβ takes place in lipid rafts: special regions of the membranes of brain cells in which cholesterol is highly concentrated. This work highlighted the benefit of restoring neuronal copper levels to reduce the accumulation of Aβ in transgenic mice, demonstrating potential therapeutic benefits of copper ionophores for treating AD.

Gawain McColl introduced Caenorhabditis elegans (C.elegans, commonly known as ‘roundworm’) as a model system for studying longevity in a brief timeframe, as the lifespan of a C.elegan is just a few weeks. Gawain will apply this model to neurodegenerative diseases including Alzheimer's and Parkinson's diseases.

Gawain collaborated with colleagues, Blaine Roberts and Adam Gunn, to characterise the truncated Aβ-peptide expressed in a C.elegans model of AD. From this, McColl and Roberts co-first authored a paper which was recently accepted for publication in the Journal of Biological Chemistry.

This research will further our understanding of how particular variants of Aβ may be involved in the AD process and its progression.

In another large-scale collaborative study with his former mentor, Associate Professor Lithgow, Gawain produced a first author manuscript describing how insulin-like signaling mechanisms determine survival during stress
in the C.elegans. Furthermore, Gawain’s successful application requesting beam-time at the Australian Synchrotron enabled him to complete a 2D elemental mapping of C.elegans across its lifespan.

These unique experiments generated the first high-resolution elemental
maps of entire C.elegans as they age.

Treating Parkinson’s disease

The laboratory is working to:

• Develop animal and cell-based models for neurodegenerative diseases such as PD and Dementia with Lewy Bodies that can be used for the testing of new drugs to treat these conditions. Both conditions contain aggregates of a protein usually found in nerve cells called alpha-synuclein.
• Examining the interactions between iron, dopamine and
  alpha-synuclein (the three players thought to be involved in the development of PD).
• Studying the way that drugs can restructure the brain to compensate for disease pathology.

Achievements

Robert Cherny and David Finkelstein obtained National Health and Medical Research Council (NHMRC) funding to develop and study new drugs for
Parkinson’s disease (PD).

In collaboration with Prana Biotechnology, they designed and tested a suite of novel compounds which have shown remarkable neuroprotective effects in two animal models of PD. These findings were presented for the first time at the Society for Neuroscience Conference in Washington
DC in 2008.