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Douglas W. Ethell, Ph.D.
Assistant Professor of Biomedical Sciences
Ph.D., The University of British Columbia, Vancouver, B.C., Canada, 1993
Max Planck Institute for Psychiatry 1993-96
The Scripps Research Institute 1996-97
The Burnham Institute 1997-99
La Jolla Institute for Allergy and Immunology 1999-2001
Email: doug.ethell@ucr.edu
Homepage: Biomedical
Sciences Homepage
Research Summary
My lab is interested in how brain cells die in disorders such as Alzheimer's disease, stroke, diabetic
neuropathy, and Multiple Sclerosis. All cells in our bodies are capable of triggering a kind of cellular
suicide, called apoptosis. This kind of proactive cell death is very important in eliminating damaged,
pre-cancerous, infected, superfluous, or otherwise unwanted cells from the body. However, inappropriate
activation of apoptosis in brain cells can eliminate important neurons and lead to clinical deficits. It
has been suggested that most neurodegenerative disorders result from such inappropriate apoptosis. We are
investigating how apoptotic cell death is activated and controlled in neurons and other brain cells, as it
relates to the disorders detailed above. For example, we have found that an apoptotic trigger thought to be
used exclusively by the immune system, may in fact be responsible for the progression of Alzheimer's disease.
The amyloid plaques that develop in Alzheimer's brain may be interpreted as a breach of the blood brain
barrier by neurons in the local area. The neurons respond to this breach by producing large amounts of Fas
ligand, perhaps to limit the immune system from damaging them. This high amount of Fas ligand will kill many
of the immune cells that come into the area and so suppress any possible immune response to the amyloid plaques.
Further, the high amounts of Fas ligand may directly kill the neurons themselves. Conversely, too little Fas
ligand may be just as bad by allowing the immune system too much access to the brain and spinal cord. In this
instance the immune system may create immune responses to viable brain cells as happens in Multiple Sclerosis.
In addition to studying Fas ligand as a regulator of immune access to the CNS, we are also studying the
activation of neuron apoptosis in stroke and diabetes.
Figure legend: A schematic representation of mechanisms involved in Alzheimer's disease (not to scale).
At the top left a large pyramidal neuron in the hippocampus makes beta-amyloid by sequential cleavage
of amyloid precursor protein (APP) by Beta-amyloid cleaving enzyme (BACE) and then gamma-secretase. Single
monomers of beta-amyloid are made throughout life, but their levels are elevated in the brains of Alzheimer's
patients. This higher concentration predisposes the beta-amyloid single monomers to form aggregates or
oligomers, and eventually plaques (green cluster below the red neuron. The green image is a from a microscope
photo of a real plaque that developed in our mouse model for Alzheimer's disease. Beta-amyloid aggregates can
also directly kill neurons (right middle) by triggering a cell suicide process called, apoptosis. Usually
beta-amyloid monomers and oligomers are removed from the brain through the blood stream. However, in Alzheimer's
disease beta-amyloid can also for aggregates in the space between two cell layers in the larger blood vessels
(arterioles), shown on the far right, called cerebral amyloid angiopathy or CAA. The formation of CAA can also
be precipitated by atherosclerosis depicted by the white clump. The aggregates of CAA continue to grow and
actually squeeze the blood vessel, restricting blood flow and making patients more susceptible to blood clots
and other causes of blockage. Lower blood flow or blockage in these vessels results in those parts of the
brain receiving less oxygen than they normally should, referred to as hypoxia. Neurons are very sensitive to
hypoxia even when it happens for hours or minutes, and they will respond by dying by apoptosis or necrosis,
through a mechanisms that relies on glutamate excitotoxicity of NMDA receptors. The new drug memantine blocks
some of this death, but it does not impact the factors leading up to this condition, or improve the underlying
pathology. However, preventing this kind of cell death can significantly slow down Alzheimer's progression.
Publications (since 2000)
- Ethell, D.W., Shippy D., Cao., C., Cracchiolo, J.R., Runfeldt, M., Blake, B., Arendash, G.W.
ABeta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice.
Neurobiology of Disease, Epub ahead, May 31, 2006.
Click Here to View Article
- Bilusova, T., Rusakov, D., Ethell, D.W., Ethell, I.M. MMP-7 Disrupts spines in hippocampal neurons
through NMDA receptor activation. J. Neurochem. 97(1): 44-56, 2006.
- Lo, H.-S., Walter, B., Nakajima, S., Yasui, A., Ethell, D.W. and Owen, L.B. Different biological
effects of two major types of UV-induced DNA damage on the induction of apoptosis and cell cycle arrest.
BMC Cancer 5: 135, 2005.
- Ethell, D.W. and Buhler, L.A. Fas ligand-mediated apoptosis in degenerative disorders of the brain.
J. Clin. Immunol. 23(5): 361-368, 2003.
- Maverakis, E.M., Stevens, D.B., van den Elzen, P., Brossay, L., Mendoza, R., Thai, Q., Macias, L.H.,
Campagnoni, C.W., Ethell, D.W., Campagnoni, A.T., Ametani, A., Sette, A. and Sercarz, E.E. Implications for
determinant capture as a mechanism of preventing negative selection of autoreactive self-repertoires:
Peptides possessing weak affinities for MHC class II molecules are effective inducers of central tolerance.
Proc. Natl. Acad. Sci. USA, 100(9): 5342-5347, 2003.
- Ethell, D.W., Kinloch, R. and Green, D.R. Metalloproteinase inhibitors increase beta-amyloid neurotoxicity
through enhancement of Fas/FasL interactions. Current Biology 12: 1595-160, 2002.
- Ethell, D.W., Bossy-Wetzel, E. and Bredesen, D.E. Caspase-7 can cleave tumor necrosis factor I (p60)
at a non-consensus motif, in vitro. Biochemica et Biophysica ACTA. 1541(3): 231-238, 2001.
- Quinn, A., Melo, M., Ethell, D.W. and Servarz, E.E. Defective peripheral tolerance in autoimmune
diabetes: Relative resistance to nasally-induced tolerance in NOD mice but not other I-Ag7-expressing
mouse strains. Int. Immunol. 13(10): 1321-1333, 2001.
- Ethell, D.W. and Green, D.R. Assessment of cytochrome c release from mitochondria. In Apoptosis
Techniques and Protocols 2nd Edition - part of the Neuromethods Series, Chapter 2, LeBlanc et al. (Eds.),
Humana Press, New York, pp. 21-34, 2001.
- Ethell, D.W. and Green, D.R. Mitochondria and Apoptosis: stepping stones on the path to apoptosis.
In Neuronal Death by Accident or by Design. Henderson et al. (Eds.), Springer-Verlag, New York, pp, 1-14, 2001.
- Wang, JJ.-L., Ethell, D.W., Chang, L., Testa, M.P., Tasinato, A. and Bredesen, D.E. (2000).
Phosphorylation of the common neurotrophin receptor p75 by p38b2 kinase affects NF-kB and AP-1 activities.
J. Mol. Neurosci. 15: 19-30, 2000.
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