Molecular Neurophysiology
MOLECULAR NEUROPHYSIOLOGY: Barrett Lab
RESEARCH INTERESTS:
Alzheimer’s disease and p75 neurotrophin receptor
Alzheimer’s disease (AD) is the most common form of dementia amongst the elderly. A characteristic feature of AD is the decline and death of cholinergic neurons, particular nerve cells in parts of the brain associated with memory, thought and language. The decreased numbers of cholinergic neurons results in a reduced production of the neurotransmitter acetylcholine, which plays an important role in learning and memory formation.
There is currently no cure for AD. Treatment focuses on relieving and slowing down the progress of the symptoms. Some of the currently approved drugs used for treating AD attempt to increase the levels of acetylcholine but become ineffective with age as the nerve cells ultimately die.
Neurotrophins have long been known to promote survival and differentiation of mammalian neurons. However, they have also been shown to induce cell death via the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily. The p75 NTR is widely expressed in the embryonic brain but not in the adult brain. Interestingly, p75NTR is re-expressed in neurodegenerative diseases such as AD, spinal cord injury and axotomy. Thus, p75NTR has a diverse range of effects ranging from cell death to regulation of axonal elongation in development.
Our lab is particularly interested in the role of p75NTR in the death of cholinergic forebrain neurons during ageing and in AD. Studies on mice that were bred to lack the p75NTR have shown that inhibition or lack of p75NTR decreased the age-related death of the cholinergic neurons, as well as increased the size of these neurons and their production of acetylcholine which has led to an improvement in spatial learning (Greferath et al, 2000). Work in progress is focussed on developing an inhibitor of p75NTR and finding a way of delivering it to the brain.
We are also interested in identifying the p75NTR signalling pathways and the intracellular proteins with which it interacts to gain an understanding of how p75NTR works in the normal and diseased brain.
Antisense oligonucleotides
The treatment of central nervous system diseases with antisense oligonucleotide therapy holds great promise. Normally, a gene codes for a messenger RNA (mRNA) which is then read by a ribosome to generate a specific protein. With antisense technology, the antisense oligonucleotide (a short DNA/RNA sequence complementary to the mRNA sequence of interest) would bind to its mRNA target, preventing its translation, thus preventing the synthesis of the protein product.
A number of factors, such as the mode of action, specificity, chemistry, and pharmacology must be carefully considered for the design and successful application of antisense oligonucleotides due to some of the problems they pose once inside the body including their susceptibility to nuclease digestion and degradative enzymes that are found within the body and the lethal side effects that can occur as a result of the inability of some antisense oligonucleotides to correctly bind to the targeted cell or tissue.
TECHNIQUES USED:
- Molecular biology
- Small animal surgery, behavioural testing
- Organic chemistry
- Histology
- Tissue culture
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A section of the mouse brain that has been double immunostained with p75 (green) and ChAT (choline acetyltransferase) (red). Neurons that express both antibodies are depicted in yellow. |
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A rat undergoing a spatial learning test known as the Barnes Maze. This is used to test the animal’s ability to learn and remember where the escape tunnel (black box) is located using various visual cues placed around the room. |
THE TEAM
Chief Investigator: Assoc. Prof. Graham Barrett
Location: N303
Email: grahamlb@unimelb.edu.au
Phone: (03) 8344 5869
Research Assistant: Mr Tim Naim
Location: N302
Email: tnaim@unimelb.edu.au
Phone: (03) 8344 4404
Research Assistant: Ms. Jennifer Trieu
Location: N302
Email: jtrieu@unimelb.edu.au
Phone: (03) 8344 4404
FUNDING:
Our research attracts both national competitive and commercial funding:
NHMRC Project Grant. How does the p75 neurotrophin receptor transmit both pro-survival
and pro-apoptotic signals in neurons?
Circadian Technologies Ltd. Development of anti-p75NTR antisense reagents and
their application in neurological disease models.
AusIndustry Biotechnology Innovation Fund (BIF) Grant. Development of treatment
for Alzheimer’s disease.
RECENT RELATED PUBLICATIONS
Barrett GL, Greferath U, Barker PA, Trieu J, Bennie A (2005) Co-expression of the p75 neurotrophin receptor and neurotrophin receptor-interacting melanoma antigen homolog in the mature rat brain. Neuroscience 132: 381-92.
Epa WR, Markovska K, Barrett GL (2004) The p75 neurotrophin receptor enhances TrkA signalling by binding to Shc and augmenting its phosphorylation. Journal of Neurochemistry 89: 344-53.
Greferath U, Mallard C, Roufail E, Rees S, Barrett GL and Bartlett P (2002). Expression of the p75 neurotrophin receptor by striatal cholinergic neurons following global ischemia in rats is associated with neuronal degeneration. Neuroscience Letters 332: 57-60.
Epa WR, Barrett GL and Bartlett PF. (2001). Oligonucleotides as inhibitors of protein synthesis. Methods in Molecular Biology 169:223-42.
Epa WR, Greferath U, Shafton A, Rong P, Delbridge LM, Bennie A, Barrett GL (2000) Downregulation of the p75 neurotrophin receptor in tissue culture and in vivo, using beta-cyclodextrin-adamantane-oligonucleotide conjugates. Antisense Nucleic Acid Drug Development 10:469-78.
Epa WR, Barrett GL, Bartlett PF (2001) Oligonucleotides as inhibitors of protein synthesis. Methods in Molecular Biology 169: 223-42.
Greferath U, Bennie A, Kourakis A, Barrett GL (2000) Impaired spatial learning in aged rats is associated with loss of p75-positive neurons in the basal forebrain. Neuroscience 100:363-73.
Greferath U, Bennie A, Kourakis A, Bartlett PF, Murphy M, Barrett GL (2000) Enlarged cholinergic forebrain neurons and improved spatial learning in p75 knockout mice. European Journal of Neuroscience 12:885-95.
Barrett GL (2000) The p75 neurotrophin receptor and neuronal apoptosis. Progress in Neurobiology 61:205-29.