Alzheimer’s disease is the most common form of dementia in old
age and affects an ever-increasing number of our population. The dementia
of Alzheimer’s disease is caused by a progressive destruction of neurons
in specific regions of the brain associated with memory, higher mental function
and personality. This neuronal cell loss is associated with the progressive
build up of two pathological insoluble lesions, ß-amyloid plaques,
composed of the 39-42 amino acid ß-amyloid peptide, and neurofibrillary
tangles, which are predominantly composed of hyper-phosphorylated tau protein.
Despite considerable research work, the biological mechanisms underlying
the build up of these pathologies and the relationship of these pathologies
to neurodegeneration in Alzheimer’s are still unknown, and unfortunately
no treatment exists that can effectively treat Alzheimer’s disease.
One of the major aims of research in our lab is to define the critical
molecular signal transduction events that go awry in the human brain
with ageing to cause neurodegeneration in Alzheimer’s disease. This is important
both in understanding the disease, but also in developing novel and effective
treatment strategies for the disease. Our work also focuses in part, on
signal transduction in other related age-related neurodegenerative disorders,
such as the taupopathies, Parkinson’s disease and Huntington’s
disease, as similar neuronal signaling pathways are emerging to be affected
in Alzheimer’s disease and these related disorders.
At present we use several experimental approaches to investigate and
characterise the relationship between key neuronal signal transduction
pathways and Alzheimer’s
disease pathology. These approaches use cell and molecular technologies
to examine signal transduction in brains of individuals who have had Alzheimer’s
disease, in transgenic animal models of Alzheimer’s disease, and
in cell systems which express mutant genes that can cause Alzheimer’s
disease. Presently this work is focused primarily upon:
- Akt/ PTEN
signal transduction in brain development, brain ageing and age-related
- Integrity of the Insulin and insulin-like
growth factor receptor signaling in adult brain function, and in
disease and related disorders;
- Characterisation of the role and regulation
of the ß- site
APP cleaving enzyme (BACE), and its relationship to amyloid-ß production
in Alzheimer’s disease;
- The role of calcium signal transduction
in Alzheimer’s disease.
- Stockley, J.H., and O’ Neill, C. Understanding BACE1: essential protease
production in Alzheimer’s disease. Cell.
Mol. Life Sci. Aug 11, 2008 [Epub ahead of print]
- Moloney, A.M., Griffin, R.J., Timmons, S., O’ Connor, R., Ravid, R, and O’ Neill, C. Defects in IGF-1 receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol. Aging May 12, 2008 [Epub ahead of print]
- Lordan, S., O’ Neill, C. and O’ Brien, N.M. Effects of apigenin, lycopene and astaxanthin on 7-beta-hydroxycholesterol-induced apoptosis and Akt phosphorylation in U937 cells. Br.
J. Nutr. 100 (2008) 287-296
- Stockley, J.H. and O' Neill C. The proteins BACE1 and BACE2 and ß-secretase
activity in normal and Alzheimer’s disease brain. Biochem. Soc.
Trans. 35 (2007) 574-576.
- Stockley J.H., Ravid R., and O’ Neill C. Altered ß-secretase enzyme kinetics, and levels of both BACE1 and BACE2 in the Alzheimer’s disease brain. FEBS
Lett., 580 (2006) 6550-6560.
- Griffin R.J., Moloney, A., Kelliher, M., Johnston, J.A, Ravid, R.,
Dockery P., O’ Connor, R. and O’ Neill, C. Activation
of Akt/PKB, increased phosphorylation of Akt substrates, and loss
and altered distribution of Akt and PTEN are features of Alzheimer’s
disease pathology. J. Neurochem., 93 (2005)
- Carmody, M., Mackrill, J.J., Sorrentino, V. and O'Neill, C. FKBP12
associates tightly with the skeletal muscle type 1 ryanodine receptor,
but not with other intracellular calcium release channels. FEBS
Lett., 505 (2001) 97-102.
- O'Neill, C., Cowburn, R., Bonkale, W., Ohm, T.G., Fastbom, J., Carmody,
M., Kelliher, M. Dysfunctional intracellular calcium homoeostasis:
a central cause of neurodegeneration in Alzheimer's disease. Biochem.
Soc. Symp. 67 (2001) 177-194.
- Cowburn, R.F., O'Neill, C., Bonkale, W.L., Ohm, T.G. and Fastbom,
J. Receptor G-protein signalling in Alzheimer's disease. Biochem.
Soc. Symp. 67 (2001) 163-175.
- Kelliher, M., Fastbom, J., Cowburn, R.F., Bonkale, W., Ohm, T.G.,
Ravid, R., Sorrentino, V. and O'Neill, C. Alterations in ryanodine
receptor calcium release channels correlate with Alzheimer's disease
neurofibrillary and ?-amyloid pathologies. Neuroscience,
92, (1999) 499-513.
- Shanahan, C., Gibson, G.E., Cowburn, R.F., Johnston, J.A., Wiehager,
B., Lannfelt, L. and O'Neill, C. G protein subunit levels in fibroblasts
from familial Alzheimer's disease patients: lower levels of the high
molecular weight Gsα isoform in patients with decreased ß-adrenergic
receptor stimulated cAMP formation. Neuroscience Letts.,
232 (1997) 33-36.
- Johnston J, Lannfelt L, Wiehager B, O’ Neill C, Cowburn R.
Amyloid precursor protein heat shock response in lymphoblastoid cell
lines bearing presenilin-1 mutations. Biochem et Biophys
Acta., 1362 (1997) 183-92.
- Cowburn R, Fowler C, O’ Neill C. Cholinergic signal transduction
mechanisms in Alzheimer’s disease. Annals of Psychiatry
6 (1996) 265-72.
- Cowburn R, Fowler C, O’ Neill C. Neurotransmitter receptor/G-protein
mediated signal transduction in Alzheimer’s disease brain. Neurodegeneration
5 (1996) 483-88.
- Gorman, A.M., McGowan, A., O’ Neill, C. and Cotter, T. Oxidative
stress and apoptosis in neurodegeneration. J. Neurol.
Sci., 139 (1996) 45-52.
- Cowburn R, O’Neill C, Fowler C. Membrane alterations as causes
of impaired signal transduction in Alzheimer’s disease and aging.
Trends in Pharmac. Sci., 18 (1995)483-4.
- Johnston J, Cowburn R, Norgren S, Wiehager B, Venizelous N, Winblad
B, Vigo-Pelfrey C, Schenk D, Lannfelt L, O’ Neill C. Increased
ß-amyloid release and levels of the amyloid precursor protein
in fibroblast cell lines from family members with the Swedish Alzheimer’s
disease APP 670/671 mutation. FEBS Letters
354 (1994) 274-8.
- Johnston J, O’ Neill C, Lannfelt L, Winblad B, Cowburn R.
The significance of the Swedish APP670/671 mutation in the development
of Alzheimer’s disease amyloidosis. Neurochem Int.,
25, (1994) 73-80.
- O’ Neill C, Fowler C, Winblad B, Cowburn R. G-protein linked
signal transduction systems in the Alzheimer’s disease brain.
Biochem. Soc. Trans., 22 (1994) 167-71
- Cowburn R, Marcusson J, Eriksson A, Wiehager B, O’ Neill C.
Adenylyl cyclase activity and G-protein subunit levels in postmortem
frontal cortex of suicide victims. Brain Res.,
633 (1994) 297-304
- O’ Neill C, Wiehager B, Fowler C, Ravid R, Winblad B, Cowburn
R. Regionally selective alterations in G protein subunit levels in
the Alzheimer’s disease brain. Brain Res.,