Research Network for Metals in Medicine

 

 

Professor Ralph Martins

Position: Adjunct Professor

Affiliation: School of Psychiatry & Clinical Neurosciences, The University of Western Australia

Postal Address:
Psychiatry & Neurogenetics
c/o Hollywood Private Hospital
115 Monash Ave.
Nedlands
Perth 6009
AUSTRALIA

Phone: +61 (08) 9346 6703
Fax: +61 (08) 9346 6666
Email: rmartins@cyllene.uwa.edu.au
Webpage: www.alzheimers.com.au


Research Profile

Professor Martins’ undergraduate and postgraduate studies were both undertaken at the University of Western Australia where he majored in Biochemistry with first class Honours followed by a PhD which examined the role of hormones and diet on the regulation of key enzymes of lipid metabolism. He was fortunate to gain part-time employment with Professor Colin Masters in 1984, who played a major role in stimulating his interest into studying the molecular pathology of Alzheimer’s disease. On completion of his PhD in 1986 he was offered full-time employment by Professor Masters as a postdoctoral fellow and subsequently as a senior research officer when he moved with him to Melbourne University in 1989. His 7 years with Professor Masters were most rewarding as he had an opportunity to undertake seminal research in a nurturing environment which involved isolating and characterizing, for the first time, the molecular components of the neuropathological hallmarks of Alzheimer’s disease. His early training in Alzheimer’s disease research was further enhanced in 1987 when he was awarded a scholarship to Heidelberg University to work with Professor Konrad Beyreuther. His collaborative seminal research involved the isolation and characterisation of ?-amyloid and its precursor, the amyloid precursor protein (APP), which are now recognized as central to the pathogenesis of Alzheimer's disease. During this same period he also was the first to propose and demonstrate that the Alzheimer brain was under oxidative stress a feature that is now widely recognized by the Alzheimer research community. Further work in this area, led to an international patent (PCT/AU02/01754) and the formation of a spin-off company, Alzhyme Pty Ltd. In 2002 year he was awarded a Biotechnology Innovation Fund grant, which was matched dollar for dollar by a commercial group.

Over the past 12 years he has established the Sir James McCusker Alzheimer’s disease Research Unit at Hollywood Private Hospital, which currently comprises 9 research staff and 9 postgraduate students whose research is directed at understanding the cause(s) developing early diagnostics and effective treatments for Alzheimer’s disease. He was instrumental in establishing the McCusker Foundation for Alzheimer’s Disease Research 3 years ago and is the Research Director of the McCusker Alzheimer Unit. He was recently appointed by Edith Cowan University to the Inaugural Chair in Ageing and Alzheimer’s Disease, a position which he commenced on the 16th January 2004. He will continue to have close ties with the clinical academics at the University of Western Australia and has been appointed to the position of Adjunct Professor, in the School of Psychiatry and Clinical Neurosciences. He will continue to enjoy an affiliation with Curtin University of Technology as Adjunct Associate Professor. In 2001 he was appointed Professor at the Research Centre and Community Services, Universitas Pelita Harapan, Karawaci, Tangerang, Indonesia which is a voluntary, non-salaried position where his role is to uplift research in the new medical faculty. He has commenced a research program at Pelita Harapan to study genetic risk factors for AD in 4 ethnic communities. In 2001 he was fortunate to be 1 of 3 candidates from 70 scientists throughout Australia to successfully win a Media Fellowship with the ABC. He was the first Media Fellow to have his work presented on the Science Show and he is now working on a part-time voluntary basis with the ABC to communicate medical science to the public. In 2003 he was appointed to the position of Senior Editor, for the Journal of Alzheimer’s disease and Editorial Board Member for Current Drug Targets CNS & Neurological Disease. He was also the recipient of the University of Western Australia "Excellence in Teaching Award - Post Graduate Research" for 2002.

His current AD-related research includes the identification of novel genes in AD, the therapeutic potential of anti-oxidant combinations and other anti-beta amyloid agents. His group has led the field in the identification of genetic risk factors for AD in the Australian population. He has published over 100 articles in peer reviewed international journals over the last 16 years.

The isolation and characterization of the molecular components beta amyloid and its parent molecule the amyloid precursor protein which was achieved by joint collaboration between the Masters team in Perth and the Beyreuther team in Cologne and Heidelberg. These seminal findings are the foundations of most current therapeutic strategies for targeting Alzheimer’s disease.

Oxidative stress is now widely regarded as a major feature of Alzheimer pathogenesis. As a postdoc in Professor Masters laboratory Martins independently investigated the notion that the Alzheimer brain is under increased oxidative stress. He was the first investigator to propose and provide evidence for increased oxidative stress in Alzheimer’s disease.

Returning to Perth he investigated the role of growth factors on collateral development and in collaboration with Dr Marilyn Sleigh from CSIRO genetically engineered the production of recombinant human plate derived growth factor which was initially used to facilitate collateral development in animal models. Other growth factors that more specifically targeted endothelial cells were then successfully used such as basic fibroblast growth factor with the most specific with the most specific of these factors namely vascular endothelial growth factor (VEGF) genetically engineered for the first time in Australia in collaboration with Dr Merilyn Sleigh. These seminal studies have subsequently been applied and tested in human clinical trials in the United States for enhancing collateral blood vessels in the hearts of patients suffering from arterial occlusions

He has devoted considerable efforts towards developing an early diagnostic test and has shown that the parent molecule of beta amyloid, the amyloid precursor protein (APP) is decreased in the blood plasma of Alzheimer’s disease patients. He has extended these findings to skin fibroblasts from patients with a strong family history of early onset Alzheimer’s disease and demonstrated for the first time that the skin fibroblasts of patients with mutations in their presenilin 1 gene exhibit altered APP metabolism resulting in increased beta amyloid secretion. Martins’ laboratory in collaboration with Professor Peter Schofield from the Garvan Institute have confirmed clinical diagnosis in the vast majority of Alzheimer patients in Australia with mutations in their presenilin 1 gene.

In addition to investigating genes that cause Alzheimer’s disease he has assessed the role of the major genetic risk factor, apoE e4, in the Australian population. His team has been the first in Australia to show that apoE e4 is associated with about 50% of late-onset Alzheimer’s disease cases. In an attempt to answer how apoE e4 exerts risk of Alzheimer’s Martins’ team have led the field internationally to show that apoE e4?unlike the other forms of apoE is very inefficient at binding beta amyloid which led us to propose that apoE e4 ?is defective at clearing beta amyloid from the extracellular space. His lab made a novel finding that in addition to the apoE genotype effect the amount of apoE produced also impacts on risk of AD.

He and others have now demonstrated a direct link between increased beta amyloid production and oxidative stress in Alzheimer’s disease. There is now strong evidence to indicate that beta amyloid contributes directly by producing hydrogen peroxide and that this action requires the binding of metal ions. While other groups are focussing on evaluating chelation therapy he has developed a novel screening procedure to obtain drug leads that target and block the interaction of beta amyloid with metal ions (PCT/AU02/01754). In 2002 year he was awarded a Biotechnology Innovation Fund grant which was matched dollar for dollar by a commercial group. He has now demonstrated that one of our lead compounds attenuates beta amyloid’s catalytic activity to generate hydrogen peroxide as well as block its neurotoxicity in cell culture. Martins’ team is now proceeding to test this compound in vivo

Selected Publications

  1. Gnjec A, Fonte J, Atwood C and Martins RN. "Transition Metal Chelator Therapy - a Potential treatment for Alzheimer's Disease". Frontiers in Bioscience (2002) 7:1016-1023
  2. Bowen RL, Smith MA, Harris PLR, Kubat Z, Martins RN, Castellani RJ, Perry G. and Atwood C S. Elevated Lutenizing Hormone Expression Colocalizes With Neurons Vulnerable to Alzheimer's Disease Pathology. Journal of Neuroscience Research (2002) 70:514-518.
  3. Sparks DL, Martins RN and Martin T. Cholesterol and cognition: rationale for the AD cholesterol-lowering treatment trial and sex-related differences in beta-amyloid accumulation in the brains of spontaneously hypercholesterolemic Watanabe rabbits. Ann. N.Y. Acad. Sci. (2002) 977:356-66.
  4. Munch G, Shepherd CE, McCann H, Brooks WS, Kwok JB, Arendt T, Hallupp M, Schofield PR, Martins RN, Halliday GM. Intraneuronal advanced glycation endproducts in presenilin-1 Alzheimer's disease. Neuroreport. (2002) 13, (5):601-4.
  5. Xie Ling, Martins R.N, Racchi M, Craft S and Helmerhorst E. Beta Amyloid antagonizes insulin promoted secretion of the amyloid precursor protein. Journal of Alzheimer's Disease (2002) 4. (5) (In press) (http://www.jalz.com/vol4 number 5.html)
  6. Atwood CS, Martins RN, Smith MA, Perry G. Related Articles Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins. Peptides. (2002) 23 (7):1343-50.
  7. Miklossy J. Taddei T, Suva D, Verdile G, Fonte J, Fisher J, Gnjec A, Ghika J, Suard F, Mehta, PD, McLean CA, Masters CL, Brooks WS and Martins RN. Two novel presenilin-1 mutations (Y256S & Q222H) are associated with early-onset Alzheimer's disease. Neurobiology of Aging. (2003) 34: 655-662. (electronic version available on net).
  8. Dean B, Laws SM, Hone E, Taddei K, Scarr E, Thomas EA, Harper C, McLean C, Masters C, Lautenschlager N, Gandy SE and Martins RN. Increased levels of apolipoprotein E in the frontal cortex from subjects with schizophrenia. Biol. Psychiatry (2003) Vol 54, 6:
  9. Thomas EA, Laws SM, Sutcliffe JG., Harper C, Dean B, McClean, C, Masters C, Lautenschlager N, Gandy SE and Martins RN. Apolipoprotein D Levels are Elevated in Prefrontal Cortex of Subjects with Alzheimer’s Disease: No Relation to Apolipoprotein E Expression or Genotype. Biol. Psychiatry (2003) 54(2):136-141.
  10. Veurink G, Atwood A, Robertson T, Groth D, Perry G and Martins RN. Reduction of inclusion body pathology in ApoE-deficient mice fed a combination of antioxidants. Free Radical Biology and Medicine (2003) 34 (8):1070-1077.
  11. Christen-Zaech S. Kraftsik R, Pillevuit O, Martins RN and Miklossy J. Early appearance of degenerative changes in the olfactory system in Alzheimer's disease. Can J Neurol Sci (2003); 30: 20-25

Facilities

The Sir James McCusker Alzheimer's Disease Research Unit at Hollywood Private has 2 laboratories, dark room, walk in cold room, culture lab, incubator room, tissue processing and sectioning room, microscope room, isotope room, 2 freezer rooms, centrifuge room, gel running and a gel drying room. Major equipment includes: Analyze 4 Complete Imaging System with laptop and workstation; Nikon Eclipse E600 Model Fluorescence Microscope with light microscope (Phase contrast as well as dark field) and digital still camera DXM1200; ultracentrifuge and airfuge ultracentrifuge, low speed refrigerated preparative centrifuges, 6 bench top centrifuges, facilities for tissue culture including capabilities for large scale hybridoma culture, multiple tissue culture incubators, inverted microscopes, various microscopes, multiple electrophoresis and transblot apparati, numerous +5 to –20oC fridge/freezers, 3 –86oC upright/chest freezers, 5 thermal (PCR) cyclers, water baths, shaking water bath, spectrophotometer, BMG fluostar Optima with modes for standard time resolved fluorescence, luminescence and Absorbance, DNA sequencing apparatus, Gel drying apparatus, ELISA microplate reader, ultrasonic cell disruptor/sonifier, homogenizers, facilities for tissue processing, embedding, sectioning and staining/immunohistochemistry, Isoelectric Focusing units includes a BioRad Protean IEF cell with supporting BioRad GS-800 calibrated Densitometer and software, audiovisual projector which is used for real and elapsed time monitoring of experiments and CAS-1200 liquid handling system. Access to all major equipment including laser capture, flow cell cytometry and electron microscopy are readily available in adjacent UWA departments.

International Linkages

  • Collaboration has been ongoing for the last 10 years with Professor Sam Gandy from the Farber Institute for Neurosciences, Thomas Jefferson University Philadelphia into an interdisciplinary approach to Alzheimer Drug discovery. The collaboration with Professor Sam Gandy has resulted in his visit in 2000 to the University of Western Australia as the Raine Visiting Professor and several joint publications including a recent publication in JAMA and the subsequent 4 month (April-July 2003) visit to Professor Gandy's Farber Institute by Professor Ralph Martins to further progress our ongoing collaborative partnership.
  • Drs Peter Hyslop and Paul Fraser from the University of Toronto to identify genetic risk factors in Alzheimer’s disease. This collaboration has involved exchange of students and staff between the University of Western Australia and the American and Canadian institutes.
  • Professor Judit Miklossy from the University Institute of Pathology, University of Laussanne in Switzerland and latterly from Center for NeuroVirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia has supplied 200 brain samples from post-mortem confirmed Alzheimer’s disease cases for biochemical and genetic studies. This collaboration has resulted in several publications.
  • The role of oestrogen in Alzheimer's disease is being undertaken in collaboration with Professor Susan Craft from the University of Washington.
  • The structure and function of the amyloid precursor protein in Alzheimer’s disease is being studied in collaboration with Professor Toshihara Suzuki of Tokyo University, Japan.
  • A study into the role of gonadotropins in the development and progression of Alzheimer's disease is being undertaken in a joint collaboration with Ass. Professor Craig Atwood from Wisconsin University Maddison Medical School, USA.
  • A recent collaboration has been instituted with Professor D. Allan Butterfield from the Dept of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington USA. This collaboration is to study oxidative stress in Alzheimer's disease and this year one of our PhD students has spent 6 months with Professor Butterfield investigating the protective effects of apoE isoforms on Abeta induced oxidative stress in cell culture.
  • Collaboration is ongoing with Associate Professor Joachim Hallmayer from Stanford University Department of Psychiatry and Behavioral Science to identify genetic and molecular risk factors in neurodegenerative diseases. This collaboration has resulted in several papers.
  • Professor Hans Forstl from Klinik und Poliklinik fur Psychiatrie und Psychoptherapie der Technischen Universitat Munchen, Munich, Germany and Dr Nicola Lautenschlager from the School of Psychiatry & Clinical Neurosciences, UWA, Dept of Old Age Psychiatry Royal Perth Hospital. Ongoing collaboration has been established with Dr Lautenschlager and Professor Forstl into identification of biomarkers for cognitive decline in subjective memory complainers.
  • Ongoing collaboration has been established with the three major research groups working on Alzheimer’s disease in Australia led by Professor Colin Masters at the University of Melbourne, Associate Professor Peter Schofield from the Garvan Institute in Sydney and Professor Tony Broe from the Prince of Wales Medical Research Institute, Sydney, New south Wales.
  • Dr Elizabeth Milward from the University of Newcastle New South Wales, ongoing research into 'Iron-related genes and neurodegenerative disorders".