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Molecular Neurobiology

Dr David Small

Welcome to the Laboratory of Molecular Neurobiology

Members of the Laboratory

Associate Professor. David H. Small, NHMRC Senior Research Fellow B, Head

Dr. Steven Petratos, Research Fellow
Dr. Danuta Maksel, Postdoctoral Fellow
Dr. Marie Beckman, Postdoctoral Fellow
Mr. Michael Azari, Research Assistant
Ms Sharon Unabia, Research Assistant
Ms Megan Kerr, PhD student
Mr. Xu Hou, PhD student
Ms Judy Ng, MSc. student

Associates of the Laboratory

Dr. Mibel Aguilar, Dept. of Biochemistry and Molecular Biology, Monash University
Dr. Lisa Martin, Dept. of Chemistry, Monash University
Dr. Patrick Perlmutter, Dept. of Chemistry, Monash University  

Research Projects in the Laboratory of Molecular Neurobiology

The central focus of our research is to understand the pathogenesis of Alzheimer's disease and related disorders and to develop
new therapies based on this understanding. We also aim to develop diagnostic techniques which can be used to discriminate
Alzheimer's disease from other dementia causing illnesses.


Fig.1. The structure of acetylcholinesterase showing inhibition
at the active site by tacrine, a drug utilised for the treatment
of Alzheimer's disease (from Sussman et al.)

One of the most important findings in the last decade has been the demonstration that a several neurodegenerative disorders share a common biochemical cause, involving aggregation and deposition of abnormal proteins. Abnormal protein deposition can lead to neuronal degeneration with a consequent loss of brain function. The protein deposits can be extracellular, (e.g., beta-amyloid protein, ABri, PrP) or intracellular (e.g., tau, alpha-synuclein, huntingtin and superoxide dismutase). Typically, the extracellular deposits form amyloid, which is an extracellular proteinaceous deposit that can bind Congo red. The discovery that this common biochemical mechanism is the cause of many neurodegenerative diseases has led to a flurry of activity in recent years aimed at targeting the production, deposition or toxic effects of these protein deposits.
 
Disease
 		 Pathology Protein
Alzheimer's disease Amyloid plaques and tangles Abeta, tau
Parkinson's dis. / Lewy body dementia Lewy bodies alpha-synuclein
Huntington's disease Intranuclear and cytoplasmic inclusions Huntingtin
Pick's disease Neurofibrillary tangles tau
Progressive supranuclear palsy Neurofibrillary tangles tau
Corticobasal degeneration Neurofibrillary tangles tau
Frontotemporal dementia Neurofibrillary tangles tau
Amyotrophic lateral sclerosis Bunina bodies SOD1
Mad cow disease, CJD Prion plaques Prion protein (PrP)

Alzheimer's disease the prototypic amyloidosis

Amyloid plaque in the brain of a patient with AD

Alzheimer's disease (AD) is the most common form of dementia. The disease is characterised by protein deposition, extracellularly as amyloid plaques and cerebral amyloid angiopathy and intracellularly as neurofibrillary tangles (NFT). NFTs are comprised of a hyperphosphorylated form of the cytoskeletal protein tau whereas the extracellular amyloid contains a 4-kDa polypeptide known as the beta-amyloid protein or Abeta, which is derived from the beta-amyloid protein precursor (APP).

The structure of APP

APP is cleaved by enzymes known as secretases, which cut on the N- and C-terminal sides of the Abeta sequence. Because of its propensity to aggregate, Abeta builds up in the brain of AD patients, ultimately forming amyloid. There is now very strong evidence that this aggregation is a key event in the pathogenesis of AD.

The Laboratory of Molecular Neurobiology has openings for Honours and PhD students in the following project areas:

  1. Amyloid - membrane studies using surface plasmon resonance
  2. Studies on amyloid structure using atomic force microscopy
  3. Development of novel peptidomimetic inhibitors of amyloidosis
  4. Development of novel peptidomimetic inhibitors of Abeta-generating enzymes
  5. Studies on the regulation of APP trafficking in neurons
  6. Signal transduction and calcium homeostasis in neurodegenerative diseases
  7. Studies on the alpha7 nicotinic acetylcholine receptor and its role in memory and synaptic plasticity
  8. Mechanisms of transthyretin amyloidosis
  9. Biochemistry of British dementia peptide and amyloidosis
  10. Identification of cerebrospinal fluid biochemical markers of Alzheimer's disease

Selected publications (total publications ~120)

  1. Small, D.H. and Carnegie, P.R. (1981) Myelopathy associated with vitamin B12 deficiency - new approaches to an old problem. Trends Neurosci. 4, Nov. X-XI.
  2. Small,D.H. and Wurtman,R.J. (1984) Serotonin binds specifically and saturably to an actin-like protein isolated from rat brain synaptosomes. Proc. Natl. Acad. Sci. USA 81, 959-963.
  3. Small,D.H. (1990) Non-cholinergic actions of acetylcholinesterases: proteases regulating cell growth and development? Trends Biochem. Sci. 15, 213-216.
  4. Small,D.H., Moir,R.D., Fuller,S., Bush,A.I., Li,Q-X, Milward,E., Hilbich,C., Weidemann, A., Beyreuther,K., Masters,C.L. (1991) A protease activity associated with acetylcholinesterase releases the membrane-bound form of the amyloid protein precursor of Alzheimer's disease. Biochemistry 30, 10795-10799.
  5. Small,D.H., Nurcombe,V., Moir,R.D., Michaelson,S., Monard, D., Beyreuther,K., Masters,C.L. (1992) Association and release of the amyloid protein precursor of Alzheimer's disease from chick brain extracellular matrix. J. Neuroscience 12, 4143-4150.
  6. Milward,E.A., Papadopoulos,R., Fuller,S., Moir,R.D., Small,D., Beyreuther,K., Masters,C.L. (1992) The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron 9, 123-127.
  7. ush, AI, Multhaup, G, Moir, RD, Williamson, TG, Small, DH, Rumble, B., Pollwein, P, Beyreuther, K & Masters, CL. (1993) Identification of a novel zinc(II) binding site on the beta-A4 amyloid protein precursor of Alzheimer's disease. J. Biol. Chem. 268, 16109-16112.
  8. Small, D.H., Nurcombe, V., Clarris, H., Beyreuther, K. & Masters, C.L. (1994) A heparin-binding domain on the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J. Neuroscience 14, 2117-2127.
  9. Small, D.H., Reed, G., Whitefield, B., Nurcombe, V. (1995) Cholinergic regulation of neurite outgrowth from isolated chick sympathetic neurons in culture. J. Neuroscience 15, 144-151.
  10. Li, Q-X., Evin, G., Small, D.H., Multhaup, G., Beyreuther, K. and Masters, C.L. (1995) Proteolytic processing of Alzheimer's disease ßA4 amyloid precursor protein in human platelets. J. Biol. Chem. 270, 14140-14147.
  11. Evin, G., Cappai R., Li, Q.X., Culvenor, J.G., Small, D.H., Beyreuther, K. and Masters, C.L. (1995) Candidate gamma-secretases in the generation of the carboxyl-terminus of the Alzheimer’s disease bA4 amyloid: possible involvement of cathepsin D. Biochemistry 34, 14185-14192.
  12. Brickman, Y., Ford, M., Small, D.H., Bartlett, P.F. and Nurcombe, V. (1995) Heparan sulfates mediate the binding of basic fibroblast growth factor to a specific receptor on neural precursor cells. J.Biol. Chem. 270, 24941-24948.
  13. Williamson, T., Mok, S.S., Henry, A., Cappai, R., Lander, A., Nurcombe, V., Beyreuther, K., Masters, C. and Small, D.H. (1996) Secreted glypican binds to the amyloid protein precursor (APP) of Alzheimer’s disease and inhibits APP-induced neurite outgrowth. J. Biol. Chem. 271, 31215-31221.
  14. Mok, S.S., Evin, G., Li, Q.X., Smith, A.I., Beyreuther, K., Masters, C.L. and Small, D.H. (1997) A novel metalloprotease in rat brain cleaves the amyloid protein precursor of Alzheimer’s disease generating amyloidogenic fragments. Biochemistry 36, 156-163.
  15. Sáez-Valero, J., Sberna, G., McLean, C.A., Masters, C.L. and Small, D.H. (1997) Glycosylation of acetylcholinesterase as diagnostic marker for Alzheimer’s disease. Lancet 350, 929.
  16. Moir, R.D., Lynch, T., Bush, A.I., Whyte, S., Henry, A., Portbury, S., Multhaup, G., Small, D.H., Tanzi, R.E., Beyreuther, K. and Masters, C.L. (1998) Relative increase in Alzheimer’s disease of soluble forms of cerebral Abeta amyloid protein precursor containing Kunitz protease inhibitory forms J. Biol. Chem. 273, 5013-5019.
  17. Sberna G., Sáez-Valero, J., Li, Q.-X., Czech, C., Beyreuther, K., McLean, C., Masters, C.L. and Small, D.H. (1998) Acetylcholinesterase is increased in the brains of transgenic mice expressing the C-terminal fragment (CT100) of the beta-amyloid protein precursor of Alzheimer’s disease. J. Neurochem. 71, 723-731.
  18. Small, D.H. and McLean, C.A. (1999) Alzheimer’s disease and the amyloid beta protein: what is the role of amyloid? J. Neurochem. 73, 443-9.
  19. Small, D.H., Mok, S.S. and Bornstein, J.C. (2001) Alzheimer’s disease and Abeta toxicity: from top to bottom. Nature Reviews Neuroscience 2, 595-598.
  20. Fodero, L.R., McLean, C.A., Robertson, T., Martins, R.N., Beyreuther, K, Masters, C.L., Robertson, T.A. and Small, D.H. (2002) Altered glycosylation of acetylcholinesterase in APP (SW) Tg2576 transgenic mice occurs prior to amyloid plaque deposition. J. Neurochem. 81, 441-448.
  21. Nunan, J and Small, D.H. (2002) Alpha-, beta- and gamma-secretases in the proteolytic processing of the amyloid beta-protein of Alzheimer's disease. in Proteases in Biology and Medicine, Essays Biochem 38 , Portland Press pp. 37-49.
  22. Subasinghe, S., Unabia, S., Barrow, C.J., Mok, S.S., Aguilar, M.I. and Small, D.H. (2003) Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes. J. Neurochem. 84, 471-479.
  23. Small, D.H. (2004) Do cholinesterase inhibitors boost synaptic scaling in Alzheimer's disease? Trends Neurosci. 27, 245-249.
  24. Hou, X., Richardson, S.J., Aguilar, M.I. and Small, D.H.  (2005) Binding of amyloidogenic transthyretin to the plasma membrane alters membrane fluidity and induces neurotoxicity. Biochemistry 44, 11618-11627.