Colin L. Masters

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Colin L. Masters
Born (1947-02-05) February 5, 1947 (age 76)
Perth, Western Australia
NationalityAustralian
Education University of Western Australia (MB BS 1970, MD 1977)
Known forneurodegenerative diseases
Awards Potamkin Prize (1990)
King Faisal International Prize in Medicine (1997)
Scientific career
Fields neuropathology
Institutions NINDS (1977-1981)
Heidelberg University (1981-2)
University of Western Australia (1981-9)
University of Melbourne (1989-)

Colin Louis MastersMD FAA AO (born 5 Feb 1947 in Perth, Western Australia) is an Australian neuropathologist who researches Alzheimer's disease and other neurodegenerative disorders. He is laureate professor of pathology at the University of Melbourne. [1] [2]

Contents

Career

Masters studied medicine at the University of Western Australia. [3] He opted for an extra year of pre-medical studies in 1967, which he spent doing neuropathology research, [4] and graduated M.B. B.S. in 1970. He completed his M.D. in medical neuropathology in 1977 after research fellowships at the University of Western Australia and Massachusetts General Hospital. After positions as visiting scientist at the National Institute of Neurological Disorders and Stroke and Humboldt fellow at Heidelberg University, he returned to Western Australia and Royal Perth Hospital in 1981 as a clinician-scientist. In 1989 he relocated to the University of Melbourne where he spent the rest of his career as consultant pathologist and professor of pathology, becoming laureate professor in 2002 and serving for six years as associate dean of research at the medical and dental school. [3]

Scientific achievements

Masters and his erstwhile colleague from Heidelberg Konrad Beyreuther were the first to characterize the amyloid protein that forms the cerebral plaques observed in Alzheimer's disease (AD) and Down's Syndrome (DS, also known as trisomy 21). [5] Known as amyloid beta (Aβ), this peptide is derived from amyloid precursor protein (APP), which was subsequently mapped to the region of chromosome 21 that is altered in DS. [6] The notion that Aβ causes AD, called the amyloid hypothesis, gained force from genetic studies that traced familial forms of the disease to variations in the APP gene. [7] Masters became a prominent proponent of the amyloid hypothesis, developing strategies for anti-Alzheimer's treatments that suppress the beta secretase and gamma secretase enzymes that cleave APP to form Aβ, or modify the interactions between metal ions and Aβ that are important for its toxic effects. Despite two decades of intensive research, however, these approaches have not yielded useful drugs. [8]

Awards

Masters and Beyreuther both received Max Planck Research Awards  [ de ] in 1991. [9] They also jointly won the 1990 Potamkin Prize [10] and the 1995 Zülch Award  [ de ]. [11] In 1997 they were awarded the King Faisal International Prize in Medicine, together with James F. Gusella, for contributions to the understanding of neurodegenerative diseases. [12] Masters won the Florey Medal in 2002. [13] In 2006, he was awarded the Grand Hamdan International Award for Medical Sciences in the field of Molecular and Cellular Pathology of Neurological Disorders. [14] He also received a Lifetime Achievement Award in Alzheimer's Disease Research from the Alzheimer's Association. [15] He is a fellow of the Australian Academy of Science, the Royal College of Pathologists in England, and the Royal College of Pathologists, Australia. [3] He was elected Fellow of the Australian Academy of Health and Medical Sciences (FAHMS) in 2015. [16] He is Honorary Doctor of Letters of the University of Western Australia (2008). [1] He was appointed Officer of the Order of Australia on Australia Day, 2017. [17]

Related Research Articles

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.

Karen K. Hsiao Ashe is a professor at the Department of Neurology and Neuroscience at the University of Minnesota (UMN) Medical School, where she holds the Edmund Wallace and Anne Marie Tulloch Chairs in Neurology and Neuroscience. She is the founding director of the N. Bud Grossman Center for Memory Research and Care, and her specific research interest is memory loss resulting from Alzheimer's disease and related dementias. Her research has included the development of an animal model of Alzheimer's.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">Gamma secretase</span>

Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Presenilin</span>

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">Semagacestat</span> Chemical compound

Semagacestat (LY-450139) was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Elan, and clinical trials were conducted by Eli Lilly. Phase III trials included over 3000 patients, but in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped.

Early-onset Alzheimer's disease (EOAD), also called Younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

The Alzheimer's disease biomarkers are neurochemical indicators used to assess the risk or presence of the disease. The biomarkers can be used to diagnose Alzheimer's disease (AD) in a very early stage, but they also provide objective and reliable measures of disease progress. It is imperative to diagnose AD disease as soon as possible, because neuropathologic changes of AD precede the symptoms by years. It is well known that amyloid beta (Aβ) is a good indicator of AD disease, which has facilitated doctors to accurately pre-diagnose cases of AD. When Aβ peptide is released by proteolytic cleavage of amyloid-beta precursor protein, some Aβ peptides that are solubilized are detected in CSF and blood plasma which makes AB peptides a promising candidate for biological markers. It has been shown that the amyloid beta biomarker shows 80% or above sensitivity and specificity, in distinguishing AD from dementia. It is believed that amyloid beta as a biomarker will provide a future for diagnosis of AD and eventually treatment of AD.

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-chair of Neurology, Director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH). Dr. Tanzi has been investigating the genetics of neurological disease since the 1980s when he participated in the first study that used genetic markers to find a disease gene. Dr. Tanzi co-discovered all three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including that responsible for Wilson’s disease. As the leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer's families leading to the identification of novel AD candidate genes, including CD33 and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led to clinical trials at Prana Biotechnology. He is also working on gamma secretase modulators for the prevention and treatment of Alzheimer's. He also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and Director the Cure Alzheimer's Fund Alzheimer's Genome Project™.

<span class="mw-page-title-main">P3 peptide</span>

p3 peptide also known as amyloid β- peptide (Aβ)17–40/42 is the peptide resulting from the α- and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques observed in Alzheimer's disease (AD) brains and pre-amyloid plaques in people affected by Down syndrome. However, p3 peptide's role in these diseases is not truly known yet.

Konrad Beyreuther is a German molecular biologist and chemist known for his work on neurodegenerative diseases.

Mathias Jucker is a Swiss neuroscientist, Professor, and a Director at the Hertie Institute for Clinical Brain Research of the University of Tübingen. He is also a group leader at the German Center for Neurodegenerative Diseases in Tübingen. Jucker is known for his research on the basic biologic mechanisms underlying brain aging and Alzheimer’s disease.

Robert David Moir was an Australian-born medical research scientist who theorized that the over-accumulation of beta-amyloid, which had formed to protect the brain against microbes, aided the development of Alzheimer's disease in the human brain.

Dennis J. Selkoe is an American physician (neurologist) known for his research into the molecular basis of Alzheimer's disease. In 1985 he became Co-Director of the Center for Neurological Diseases and from 1990, Vincent and Stella Coates Professor of Neurological Diseases at Harvard Medical School. He is also a Fellow of the AAAS and a member of the National Academy of Medicine.

Sylvain E. Lesné is a French neuroscientist and associate professor at the Department of Neuroscience at the University of Minnesota (UMN) Medical School, known for his research into Alzheimer's disease. He is the primary author of a 2006 Nature paper that is foundational in the hypothesis that one specific toxic oligomer of the amyloid beta protein, known as Aβ*56, is a cause of memory impairment in Alzheimer's, aligned with the prevailing amyloid hypothesis.

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

References

  1. 1 2 "Prof Colin Masters". The University of Melbourne. Retrieved 29 September 2018.
  2. ↑ "Masters, Colin L. (1947-) - People and organisations". Trove. 11 December 1947. Retrieved 30 September 2018.
  3. 1 2 3 Walker, Rosanne (26 March 2007). "Biographical entry - Encyclopedia of Australian Science". Masters, Colin Louis. Retrieved 30 September 2018.
  4. ↑ "Colin Masters Interview - Special Topic of Alzheimer's Disease". ScienceWatch.com. 25 May 2011. Retrieved 1 October 2018.
  5. ↑ Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985). "Amyloid plaque core protein in Alzheimer disease and Down syndrome". Proc Natl Acad Sci U S A. 82 (12): 4245–9. doi: 10.1073/pnas.82.12.4245 . PMC   397973 . PMID   3159021.
  6. ↑ Tanzi RE, Bertram L (2005). "Twenty Years of the Alzheimer's Disease Amyloid Hypothesis: A Genetic Perspective". Cell. Elsevier BV. 120 (4): 545–555. doi: 10.1016/j.cell.2005.02.008 . ISSN   0092-8674. PMID   15734686.
  7. ↑ Goate A; et al. (1991). "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease". Nature. Springer Nature. 349 (6311): 704–706. doi:10.1038/349704a0. ISSN   0028-0836. PMID   1671712. S2CID   4336069.
  8. ↑ Makin S (2018). "The amyloid hypothesis on trial". Nature. Springer Nature. 559 (7715): S4–S7. doi: 10.1038/d41586-018-05719-4 . ISSN   0028-0836. PMID   30046080.
  9. ↑ "Max-Planck-Forschungspreis" [Max Planck Research Award]. Max-Planck-Gesellschaft (in German). Archived from the original on 25 September 2009. Retrieved 30 September 2018.
  10. ↑ "Awards History". American Academy of Neurology. Retrieved 30 September 2018.
  11. ↑ "Zülch Prize". Max-Planck-Gesellschaft. 26 September 2018. Retrieved 30 September 2018.
  12. ↑ "Professor Colin L. Masters". King Faisal Prize. 10 October 2012. Retrieved 13 August 2018.
  13. ↑ "CSL Florey Medal 2002 – Professor Colin Masters". Australian Institute of Policy and Science. Archived from the original on 30 September 2018. Retrieved 30 September 2018.
  14. ↑ "Prof. Colin Masters". Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences. Retrieved 30 September 2018.
  15. ↑ Strobel, Gabrielle (13 September 2006). "Madrid: Pooled Antibody Cocktail, New Metal Quencher" . Retrieved 30 September 2018.
  16. ↑ "Fellowship of the Australian Academy of Health & Medical Sciences - October 2015" (PDF). Australian Academy of Health & Medical Sciences. Retrieved 12 October 2018.
  17. ↑ "2017 Australia Day honours list: Julia Gillard appointed an AC". The Sydney Morning Herald. 25 January 2017. Retrieved 30 September 2018.


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